- Email: [email protected]
Duration of Venous Thromboembolism Prophylaxis After Surgery
Duration of Venous Thromboembolism Prophylaxis After Surgery* Clive Kearon, MD
Venous thromboembolism (VTE) prophylaxis is indicated while in the hospital after major surgery. There is evidence that the prevalence of asymptomatic deepvein thrombosis, detected by routine venography after major orthopedic surgery, is lower at hospital discharge in patients who have received 10 days rather than 5 days of prophylaxis. This observation supports the current American College of Chest Physicians (ACCP) recommendation for a minimum of 7 to 10 days of prophylaxis after hip and knee replacement, even if patients are discharged from the hospital within 7 days of surgery. As risk of VTE persists for up to 3 months after surgery, patients at high risk for postoperative VTE may benefit from extended prophylaxis (eg, an additional 3 weeks after the first 7 to 10 days). Extended prophylaxis with low-molecular-weight heparin (LMWH) reduces the frequency of postdischarge VTE by approximately two thirds after hip replacement; however, the resultant absolute reduction in the frequency of fatal pulmonary embolism is small (ie, estimated at 1 per 2,500 patients). Indirect evidence suggests that, compared with LMWH, efficacy of extended prophylaxis after hip replacement is greater with fondaparinux, similar with warfarin, and less with aspirin. Extended prophylaxis is expected to be of less benefit after knee than after hip replacement. In keeping with current ACCP recommendations, at a minimum, extended prophylaxis should be used after major orthopedic surgery in patients who have additional risk factors for VTE (eg, previous VTE, cancer). If anticoagulant drug therapy is stopped after 7 to 10 days, an additional month of prophylaxis with aspirin should be considered. (CHEST 2003; 124:386S–392S) Key words: aspirin; deep vein thrombosis; heparin; low-molecular-weight heparin; prophylaxis; surgery venous thromboembolism; warfarin Abbreviations: ACCP ⫽ American College of Chest Physicians; DVT ⫽ deep vein thrombosis; INR ⫽ international normalized ratio; LMWH ⫽ low-molecular-weight heparin; PE ⫽ pulmonary embolism; VTE ⫽ venous thromboembolism *From the McMaster Clinic, Henderson General Hospital, Hamilton, ON, Canada. Dr. Kearon is supported by a Research Scholarship from the Heart and Stroke Foundation of Canada, and he has received an honorarium from the American College of Chest Physicians for the preparation of this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Clive Kearon, MD, McMaster Clinic, 70 Wing, Henderson General Hospital, 711 Concession St, Hamilton, ON, L8V 1C3 Canada; e-mail: [email protected] 386S
thromboembolism (VTE), which includes deep V enous vein thrombosis (DVT) and pulmonary embolism (PE), is an important complication of major surgery. Postoperative VTE can be prevented using pharmacologic and mechanical methods; by avoiding the need to treat patients who acquire nonfatal DVT and PE, prophylaxis reduces costs1,2 as well as saves lives.3–5 Based on assessment of patient-related and surgical factors, individual risk of postoperative VTE can be stratified as low, moderate, or high.6,7 There is widespread agreement that patients who are at moderate or high risk for postoperative VTE should receive prophylaxis while in the hospital.6 It has been proposed that patients with a high risk of postoperative VTE should also receive prophylaxis after they leave the hospital. However, it is uncertain which high-risk patients should receive postdischarge prophylaxis, which method of prophylaxis should be used, and for how long prophylaxis should be continued after leaving the hospital. This review describes the natural history of postoperative VTE, evaluates evidence relating to the use of various methods and durations of prophylaxis in different groups of high-risk surgical patients, and makes recommendations about the use of prophylaxis after hospital discharge. It focuses primarily on patients who have had major hip or knee surgery, as these patients have been well studied and are thought to have the most to gain from extended prophylaxis.6
Natural History and Epidemiology of Postoperative VTE Elements of the natural history and epidemiology of postoperative VTE that may influence decisions about the use and duration of prophylaxis after surgery are summarized in Table 1.7–37 General conclusions that can be drawn from this evidence include the following: (1) the risk of VTE differs with the type of surgery and among patients: patients with a high risk for postoperative VTE can be identified before they have surgery; (2) the risk of VTE is highest soon after surgery: prophylaxis while in the hospital prevents more thromboembolic events than prophylaxis after leaving the hospital; (3) the time course for development of postoperative VTE may differ with the type of surgery: a risk of VTE that remains high for a long time after a particular type of surgery favors more prolonged prophylaxis; and (4) the greater the number of days of postoperative prophylaxis, the lower the prevalence of asymptomatic DVT when prophylaxis is stopped: a minimum duration of prophylaxis may be indicated after high-risk surgery.
Frequency of Symptomatic VTE After Major Orthopedic Surgery in Patients Who Receive Recommended Prophylaxis for 7 to 10 Days The American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy currently recommends use of low-molecular-weight heparin (LMWH) or warfarin (target international normalized ratio [INR], 2.0 to 3.0) for at least 7 to 10 days after
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
Table 1—Natural History and Epidemiology of Postoperative VTE Half of symptomatic VTEs occur in patients who are in the hospital or a nursing home (approximately 40%), or within 3 months of leaving the hospital (approximately 10%).7,8 Half of hospital-associated VTEs occur in surgical, and half occur in nonsurgical patients.7,8 Surgical risk factors for VTE include complexity of surgery,9 general vs regional anesthesia,10,11 and associated venous trauma.12 Patient risk factors for VTE include previous VTE,13,14 cancer,10,13 estrogen therapy including tamoxifen,15,16 thrombophilia,13,17 obesity,10,13,14 advanced age,10,13,14,18 poor mobilization,13,14 and female gender.14,18,19 Major orthopedic surgery is associated with approximately twice as high a risk of VTE as general surgery.4,18,20 Postoperative DVT usually starts in the calf or, less commonly, at the site of venous trauma.12,21–23 Three fourths of DVT that occur after major orthopedic surgery are in the operated leg.23,24 A large proportion (perhaps one half) of DVTs that are associated with surgery start intraoperatively, and many of these resolve spontaneously (approximately half within 72 h).21,25,26 Use of prophylaxis after surgery facilitates spontaneous lysis of perioperative thrombi and prevents new thrombi from starting. For example, compared to those who received ⱕ 5 d of LMWH or fondaparinux after hip or knee replacement, the proportion of patients with venographically detected DVT at hospital discharge decreased by 22% with 6 to 8 d, and by 34% with 9 to 11 d of prophylaxis.27 The risk of progression of postoperative venous thrombosis appears to be greater if the initial thrombosis is large, and if there are continuing risk factors for thrombosis (eg, immobilization).21,26,28 The risk of symptomatic VTE is generally highest within 2 wk of surgery, and remains elevated for about 2 to 3 mo.3,5,18,29–31 Without prophylaxis, the highest risk period for fatal postoperative PE appears to be approximately 3 to 7 d following surgery.3,5,32–34 Risk of VTE drops more rapidly after knee replacement than after hip replacement.18,35 Among hip and knee replacement patients who receive prophylaxis while in the hospital: (1) The frequency of venographically detected (asymptomatic) DVT at hospital discharge is twice as high after knee than after hip replacement (eg, all DVT, 39% vs 16%; proximal DVT, 8% vs 4%35); (2) The frequency of symptomatic VTE while in the hospital is similar after knee and hip replacement (eg, prospective studies: knees 1.3% vs hips 1.0%35; retrospective epidemiological study: knees 1.1% vs hips 0.7%18); (3) The frequency of symptomatic DVT or PE after hospital discharge is higher after hip than after knee replacement (eg, clinical trials: hips 2.5% vs knees 1.4%35; retrospective epidemiologic study: hips 2.1% vs knees 1.0%)18; (4) Among patients who received prophylaxis, median time to occurrence of symptomatic DVT was 7 d after knee replacement and 17 d after hip replacement.18 Of hip replacement patients without DVT at hospital discharge (normal venogram) who do not continue prophylaxis, approximately 15% have DVT on venography that is performed 3 wk later, and approximately one third of these are proximal.29,30,36 Absence of DVT on venography at hospital discharge approximately 11 d after major orthopedic surgery was associated with a subsequent risk of symptomatic VTE of 1.3% (30 of 2,361 patients) during 8 wk of follow-up in patients who stop prophylaxis (studies from early 1990s).37 Symptomatic VTE is approximately 50% higher after fractured hip surgery (average age, 79 yr) than after hip or knee replacement (average age, 67 yr).5
elective hip or knee replacement, or surgery for hip fracture.6 A minimum of 7 to 10 days is recommended because this was the duration of prophylaxis that was administered before leaving the hospital in studies6,35 that established the efficacy of LMWH and warfarin after major orthopedic surgery. Length of hospital stay after hip or knee replacement has decreased during the last 10 years, and now many patients are discharged from the hospital on, or before, the fifth postoperative day (see the article by F.A. Anderson in this supplement). In order to receive the minimum recommended duration of prophylaxis of 7 to 10 days, these patients need to receive additional days of prophylaxis with LMWH or warfarin after hospital discharge. In order to decide if prophylaxis is warranted after the initial 7 to 10 days, it is important to know the expected frequency of VTE after orthopedic surgery if prophylaxis is not extended. This frequency can be estimated from prospective studies and from a large epidemiologic study.
symptomatic VTE within 3 months of surgery in a total of 6,089 patients who had undergone hip (approximately 4,500) or knee (approximately 1,500) replacement and received LMWH40 – 42 or warfarin38 – 41 for 7 to 10 days. Predischarge screening to detect asymptomatic DVT or PE was not performed in these studies, thereby avoiding the possibility that the results of such tests could have led to overdiagnosis of asymptomatic VTE or, conversely, that treatment of asymptomatic VTE could have reduced the subsequent frequency of symptomatic VTE.42 The overall frequency of symptomatic VTE within 3 months of surgery was 3.2%; 1.1% occurred while receiving prophylaxis in the hospital and 2.2% occurred during about 80 days of follow-up after stopping prophylaxis and leaving the hospital.35 Confirmed fatal PE occurred in 0.1% of patients: 0.04% while in the hospital and 0.06% after leaving the hospital.35
Prospective Studies
In a study of linked hospital records by White and colleagues,18 2.4% of patients who had undergone hip (20,000 patients) or knee (24,000 patients) replacement had a symptomatic VTE within 3 months of surgery; 0.9%
Douketis and colleagues35 analyzed data from four prospective studies38 – 41 that assessed the frequency of www.chestjournal.org
Retrospective Epidemiologic Study
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occurred while in the hospital, and 1.5% occurred after leaving the hospital.18 Eighty-eight percent of inpatients and 32% of outpatients were estimated to have received prophylaxis.18 Differences in Risk and Timing of Symptomatic VTE After Hip and After Knee Surgery: There is convincing evidence that the timing of VTE differs after hip and knee surgery (Table 1). In the early postoperative period, knee replacement is associated with at least as high a risk of symptomatic VTE as hip surgery (prospective studies35: knees, 1.3%; hips, 1.0%; epidemiologic study18: knees, 1.1%, hips, 0.7%). However, the risk of symptomatic VTE after hospital discharge is close to twice as great after hip replacement (prospective studies35: hip, 2.5%, knees, 1.4%; epidemiologic study18: hips, 2.1%, knees, 1.0%). Frequency of Symptomatic VTE After Leaving Hospital: Based on the above data, the following are reasonable estimates for the expected frequency of different presentations of symptomatic VTE within 80 days of hospital discharge if LMWH or warfarin therapy is stopped after 7 to 10 days: hip replacement–symptomatic DVT or PE, approximately 2.4%; symptomatic nonfatal PE, approximately 0.6%; fatal PE, approximately 0.06% (Table 2); knee replacement–symptomatic DVT or PE, approximately 1.4%; symptomatic nonfatal PE, approximately 0.4%; fatal PE, approximately 0.04%.
Efficacy and Safety of Different Methods of Extended Prophylaxis After Major Orthopedic Surgery LMWH The efficacy and safety of extended prophylaxis with LMWH has been evaluated after hip and knee replacement in eight controlled studies.24,29,30,36,41,43– 45 The findings of these studies, and of a study46 evaluating extended prophylaxis with unfractionated heparin, have been combined in a meta-analysis by Eikelboom and colleagues.47 Extended prophylaxis reduced the frequency of asymptomatic DVT by 51% (from 19.6 to 9.6%), symptomatic VTE by 62% (from 3.3 to 1.3%), and symptomatic PE by 57% (0.62 to 0.15%).47 It is possible that the frequency of symptomatic VTE reported by many of these studies was
influenced by the results of tests that were performed to screen for asymptomatic VTE. In an analysis of these studies that was designed to avoid this possibility, O’Donnell and colleagues42 found a lower absolute, but a similar proportional, risk reduction with extended prophylaxis after hip replacement. A reasonable estimate, therefore, is that an additional 3 weeks of LMWH therapy after the first 7 to 10 days of prophylaxis will reduce the frequency of symptomatic VTE by close to two thirds after major orthopedic surgery (Table 2). However, knee replacements accounted for less than one third of patients in these studies, and as extended LMWH appears to be less effective among those who had a knee replacement (risk reduction: 26% for symptomatic VTE, and 16% for asymptomatic DVT47), the efficacy of extended prophylaxis after knee replacement is uncertain. Provided patients with contraindications are not treated, extended prophylaxis with LMWH does not appear to be associated with increased major bleeding after orthopedic surgery, although minor bleeding is approximately 50% more common (3.4% vs 2.7%).47 Extended prophylaxis with LMWH has also been shown to reduce the frequency of VTE by approximately two thirds after surgery for cancer; the frequency of asymptomatic and symptomatic VTE in these patients was lower than after orthopedic surgery.48
Warfarin Although warfarin (target INR, 2.0 to 3.0) is widely used for extended prophylaxis after orthopedic surgery (see the article by F. A. Anderson in this supplement), to my knowledge there are no controlled studies evaluating warfarin in this setting. Warfarin appears to be less effective and associated with less bleeding than LMWH within a week of hip or knee replacement,6,40 both of which may be explained by the delayed onset of anticoagulation with warfarin. However, three sources of evidence suggest that warfarin is likely to have a similar efficacy to LMWH for extended prophylaxis. First, 7 to 10 days of warfarin therapy appears to be associated with a similar frequency of symptomatic VTE within 3 months of hip and knee replacement as 7 to 10 days of LMWH.6,40 Second, warfarin is very effective for the secondary prevention of VTE.49,50 Third, in a large casecontrol study,14 use of warfarin after hospital discharge was associated with an odds ratio of 0.6 for hospital readmission
Table 2—Postdischarge Frequency of Symptomatic VTE per 10,000 Hip Replacements (Number Needed to Treat to Prevent One Event)* Extended Prophylaxis Event
Control
DVT/PE PE Fatal PE
240 60 6
Aspirin 160 (125)† 40 (500)† 4 (5,000)†
LMWH/Warfarin
Pentasaccharide
80 (62) 20 (250) 2 (2,500)
24 (46) 6 (185) 0.6 (1,850)
*Postdischarge frequency of symptomatic VTE, 2.4%; PE, 0.6%; and fatal PE, 0.06%. Risk reduction is for VTE of one third (0.33%) for aspirin, two thirds (0.67%) for LMWH/warfarin, and nine tenths (90%) for fondaparinux. †Number needed to treat with aspirin compared to no extended prophylaxis (control) to prevent one symptomatic VTE event is the same as the number needed to treat with LMWH/warfarin compared to aspirin. 388S
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
with symptomatic VTE after hip replacement. Given that recent surgery is a risk factor for anticoagulant-induced bleeding, it is probable that extended prophylaxis with warfarin is associated with an increase in major bleeding51; however, it is not known how this risk compares with other antithrombotic agents that may be used in this setting.
Aspirin Aspirin is not recommended for prevention of VTE during the first 7 to 10 days after orthopedic surgery, as there are more effective methods available, such as LMWH and warfarin.6 Although aspirin is also likely to be less effective than LMWH and warfarin for extended prophylaxis, it has the advantages of simplicity, low cost, and safety. In the Pulmonary Embolism Prevention trial5 which included 13,000 patients with hip fracture and 4,000 patients with hip or knee replacement, aspirin reduced the risk of symptomatic VTE by 36%, and fatal PE by 53%. This effect persisted over the 35 days of aspirin use. These findings are consistent with the results of the Antiplatelet Trialists’ Collaboration,20 in which antiplatelet therapy reduced postoperative DVT by 26% and PE by 63% in an overview of 60 studies. Therefore, a reasonable estimate is that, following an initial 7 to 10 days of LMWH or warfarin therapy, a month of aspirin therapy (81 to 325 mg/d) will reduce the frequency of postdischarge symptomatic VTE by one third (Table 2). Aspirin was associated with an increase in minor GI bleeding in the Pulmonary Embolism Prevention trial5 (absolute increase of 0.9%).
Graduated Compression Stockings Although graduated compression stockings substantially reduce the frequency of leg scanning-detected DVT after general surgery, they are of uncertain, or little, benefit after hip or knee replacement.6 Graduated compression stockings cannot be recommended as a method of extended prophylaxis after orthopedic surgery.
Fondaparinux (Synthetic Pentasaccharide) Fondaparinux has been shown to be more effective than LMWH for the first 7 to 10 days of prophylaxis after major orthopedic surgery, but was associated with a small additional risk of bleeding that was attributable to administering the first dose ⬍ 6 h after surgery.51 A recently completed placebo-controlled study52 showed that extended prophylaxis with fondaparinux after hip fracture surgery reduced the frequency of asymptomatic DVT by 96% and symptomatic VTE by 89% (from 2.7% to 0.3%). Extended prophylaxis with fondaparinux was associated with a tendency to increased bleeding compared to placebo bleeding (major bleeding, 2.4% vs 0.6%).52
Improving the Risk/Benefit Ratio of Extended Prophylaxis The main risk associated with extended-prophylaxis is bleeding, and the main benefit is prevention of VTE. Therefore, the risk/benefit ratio of extended prophylaxis improves if a greater number of episodes of VTE are prevented and/or fewer bleeds are caused. www.chestjournal.org
Preventing More Episodes of VTE Assuming that the proportional risk reduction does not decline, the absolute reduction in number of episodes of VTE achieved by extended prophylaxis increased with the patients risk of VTE. Consistent with this concept, the ACCP recommends that, at a minimum, patients with a high risk of VTE after hip or knee replacement should receive extended prophylaxis.6 Previous VTE and active malignancy are the most potent risk factors for postoperative VTE.7,10,14 Tamoxifen and hormonal replacement therapy also appear to substantially increase the risk of postoperative VTE, and withdrawing treatment with these agents for a month before and after surgery is expected to reduce this risk.15,16 Advanced age,7,10,14,18 obesity,7,10,14 poor mobilization,7,14 and female gender14,18,19 are less potent risk factors for VTE.
Avoiding Bleeding Presence of risk factors for bleeding argues against use of extended prophylaxis. Concern about bleeding at the surgical site is expected to be the most important risk factor for bleeding. Others include previous GI bleeding, poor control of warfarin therapy, or renal failure.35 The influence of risk factors for VTE and/or bleeding on choice of extended prophylaxis is summarized in Table 3.
Benefit to Preventing Asymptomatic DVT Most DVTs that occur after surgery do not progress to cause symptomatic DVT or PE. For example, using the estimates previously presented for patients who receive 7 to 10 days of LMWH therapy, the ratio of asymptomatic DVT at hospital discharge to development of symptomatic VTE within the next 3 months is about 6:1 for hip replacement and 28:1 for knee replacement. The clinical importance of asymptomatic isolated calf and proximal DVTs that, in the short term, do not progress to symptomatic DVT or symptomatic PE is uncertain. Such thrombi could increase the long-term risk of symptomatic VTE or could cause the postthrombotic syndrome. Ginsberg and colleagues54 compared the prevalence of the postthrombotic syndrome among patients who had no DVT (164 patients), asymptomatic calf DVT (66 patients), or asymptomatic proximal DVT (75 patients) on venograms performed at hospital discharge after major orthopedic surgery. Patients who were found to have DVT at venography had been treated with anticoagulant therapy for up to 3 months. An average of 5 years later, prevalence of the postthrombotic syndrome was 4% in those without DVT, 6% in those with isolated calf DVT, and 4% in those with proximal DVT, suggesting that treated asymptomatic DVTs rarely cause the postthrombotic syndrome. However, it is uncertain if this is also true for asymptomatic DVTs that are not treated. It is not known if untreated asymptomatic postoperative DVTs predispose to symptomatic VTE years later. As treated symptomatic postoperative DVTs, particularly if confined to the calf, are associated with a low risk of recurrence,55,56 it is unlikely that asymptomatic DVTs predispose to remote episodes of VTE. CHEST / 124 / 6 / DECEMBER, 2003 SUPPLEMENT
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Table 3—Factors Influencing Use and Method of Extended Prophylaxis After Major Orthopedic Surgery* Variables Risk factors for VTE Previous VTE Cancer (active) Tamoxifen or estrogen therapy† Hip vs knee surgery Known thrombophilia Slow mobilization or obesity Risk factors for bleeding Uncertain surgical site hemostasis Previous GI bleeding Cost concerns Difficulty with injections Poor access to INR monitoring Poor patient compliance Patient preference
Fondaparinux
LMWH
Warfarin
Aspirin
None
⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹
⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹
⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹
⫹ ⫹ ⫹ ⫹ ⫹ ⫹
⫺⫺ ⫺⫺ ⫺⫺
⫺⫺ ⫺ ⫹⫹ ⫺⫺
⫺⫺ ⫺ ⫹⫹ ⫺⫺
⫺⫺ ⫺ ⫹
⫺ ⫺
⫺
⫹/⫺
⫹/⫺
⫹/⫺
⫹/⫺
⫺⫺ ⫺⫺ ⫹/⫺
⫺⫺
⫺
*⫹⫹⫹ ⫽ strongly favors; ⫹⫹ ⫽ moderately favors; ⫹ ⫽ weakly favors; ⫺ ⫽ weakly discourages; ⫺⫺ ⫽ moderately discourages; no symbol ⫽ neutral influence. †Consider withholding tamoxifen or estrogen therapy for 1 month before and after surgery.
Recommended Duration of Prophylaxis After Major Orthopedic Surgery The Sixth ACCP Consensus Conference on Antithrombotic Therapy,6 which was published in January 2001, makes two main recommendations about the duration of anticoagulant prophylaxis after major orthopedic surgery. The first recommendation, which relates to the minimum duration of initial prophylaxis with LMWH or warfarin (target INR, 2.5; range, 2.0 to 3.0) is as follows: “The optimal duration of anticoagulant prophylaxis after total hip or knee replacement surgery is uncertain, although at least 7 to 10 days of prophylaxis is recommended (grade 1A).” The second recommendation, which relates to the use of extended prophylaxis, is as follows: “Extended out-of-hospital LMWH prophylaxis (beyond 7 to 10 days after surgery) may reduce the incidence of clinically important thromboembolic events, and we recommend this approach at least for high-risk patients (grade 2A because of uncertainty regarding cost-effectiveness).” Both of these recommendations still appear to be valid; however, both are open to interpretation. In the remainder of this review, I will suggest approaches to the implementation of these recommendations that reflect my interpretation of current evidence and consider differences among patients and between surgical centers.
Method of Initial Prophylaxis In the absence of a contraindication, anticoagulant therapy is the preferred method of initial prophylaxis after hip or knee replacement or surgery for hip fracture; fondaparinux may be added to LMWH and warfarin as appropriate options. Aspirin is not an adequate initial method of prophylaxis.
Duration of Initial Prophylaxis Anticoagulant prophylaxis should be used for a minimum of 7 days, and 10 days is expected to be superior. This usually 390S
requires that prophylaxis is continued for some days after hospital discharge. A minimum of 10 days rather than 7 days of prophylaxis should be considered if there is a delay (eg, ⬎ 24 h) between surgery and when LMWH or fondaparinux therapy is started, or if warfarin is used. Anticoagulant prophylaxis should also be continued while in the hospital, even if hospital discharge is markedly delayed.
Method of Extended Prophylaxis Based on indirect comparisons, fondaparinux is expected to be more effective than LMWH but may be associated with more bleeding. LMWH therapy reduces the frequency of symptomatic VTE substantially, without causing an increase of major bleeding. Warfarin is expected to be as effective as LMWH but may cause more bleeding during extended prophylaxis. If the decision has been made not to continue fondaparinux, LMWH, or warfarin therapy beyond 7 to 10 days, switching to aspirin for a month of extended prophylaxis is recommended (unless there is a contraindication). The decision to use extended prophylaxis with fondaparinux, LMWH, warfarin, or aspirin, or not to use any form of extended prophylaxis, is influenced by many factors that are summarized in Table 3. Currently, our practice is to extend anticoagulant prophylaxis to 4 weeks after hip or knee replacement or hip fracture if patients have a particularly high risk of VTE, as evidenced by a previous VTE or active malignancy (often a pathologic hip fracture), provided they do not have a high risk of bleeding. This selective approach to the use of extended anticoagulant prophylaxis is considered conservative by many; a more liberal approach, including use of such prophylaxis in all major orthopedic patients who are not at high risk for bleeding, is also reasonable. If we do not extend anticoagulant prophylaxis, we routinely recommend aspirin (80 mg/d or 325 mg/d) for a month after completing 7 to 10 days of initial prophylaxis with anticoagulants. We do not use
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
aspirin if there are concerns about aspirin intolerance or if there is a history of GI bleeding.
Duration of Extended Prophylaxis The longer that prophylaxis is administered, the more effective it is expected to be. Whereas the decision is usually to stop at 7 to 10 days, or to continue prophylaxis for approximately 4 weeks, these two options should not be applied rigidly. Extended prophylaxis for ⬍ 4 weeks is expected to be more effective than stopping at 10 days and may be appropriate for some patients (eg, out-of-hospital prophylaxis is poorly tolerated). Longer than 4 weeks of prophylaxis may be indicated for discharged patients who remain at high risk for VTE (eg, very immobile with additional risk factors).
Standardized Approach to Initial and Extended Prophylaxis at Individual Hospitals Decisions about VTE prophylaxis are influenced by, and impact on, a large number of health-care providers, including surgeons, anesthesiologists, anticoagulation services, nurses, community services, family doctors, pharmacists, and hospital administration, as well as patients and their families. While it is important that there is the flexibility to tailor management in individual patients, in order to avoid confusion and ensure that all patients receive appropriate prophylaxis, provision of prophylaxis should be standardized as much as possible within each hospital. This requires close communication and cooperation among all parties.
References 1 Salzman EW, Davies GC. Prophylaxis of venous thromboembolism: analysis of cost effectiveness. Ann Surg 1980; 191:207–218 2 Drummond M, Aristides M, Davies L, et al. Economic evaluation of standard heparin and enoxaparin for prophylaxis against deep vein thrombosis in elective hip surgery. Br J Surg 1994; 81:1742–1746 3 Kakkar VV, Corrigan TP, Fossard DP. Prevention of fatal postoperative pulmonary embolism by low doses of heparin: an international multicentre trial. Lancet 1975; 2:45–51 4 Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988; 318:1162–1173 5 Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302 6 Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119:132S–175S 7 Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000; 83:657– 660 8 Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162:1245–1248 9 Field ES, Nicolaides AN, Kakkar VV, et al. Deep vein thrombosis in patients with fractures of the femoral neck. Br J Surg 1972; 59:377 10 Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip www.chestjournal.org
replacement. N Engl J Med 1997; 337:1329 –1335 11 Modig J, Hjelmstedt A, Sahlstedt B, et al. Comparative influences of epidural and general anesthesia on deep venous thrombosis in pulmonary embolism after total hip replacement. Acta Chir Scand 1981; 147:125–130 12 Stamatakis JD, Kakkar V, Sagar S, et al. Femoral vein thrombosis and total hip replacement. BMJ 1977; 2:223–225 13 Kearon C. Natural history of venous thromboembolism. Semin Vasc Med 2001; 1:27–37 14 White RH, Gettner S, Newman JM, et al. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med 2000; 343:1758 –1764 15 Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132:689 – 696 16 Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131–2139 17 Svensson PJ, Benoni G, Fredin H, et al. Female gender and resistance to activated protein C (FV:Q506) as potential risk factors for thrombosis after elective hip arthroplasty. Thromb Haemost 1997; 78:993–996 18 White RH, Romano PS, Zhou H, et al. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998; 158:1525–1531 19 Eriksson BI, Ekman S, Ka¨ lebo P, et al. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347:635– 639 20 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994; 308:235–246 21 Kakkar VV, Howe CT, Flanc C, et al. Natural history of postoperative deep-vein thrombosis. Lancet 1969; 2:230 –232 22 Nicolaides AN, Kakkar VV, Field ES, et al. The origin of deep vein thrombosis: a venographic study. Br J Radiol 1971; 44:653– 663 23 Cruickshank MK, Levine MN, Hirsh J, et al. An evaluation of impedance plethysmography and 125I-fibrinogen leg scanning in patients following hip surgery. Thromb Haemost 1989; 62:830 – 834 24 Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement: Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001; 83:336 –345 25 Flanc C, Kakkar VV, Clarke MB. The detection of venous thrombosis of the legs using 125-I fibrinogen. Br J Surg 1968; 55:742–747 26 Maynard MJ, Sculco TP, Ghelman B. Progression and regression of deep vein thrombosis after total knee arthroplasty. Clin Orthop 1991; 273:125–130 27 Eriksson BI, Bauer KA, Lassen MR, et al. Influence of the duration of fondaparinux (Arixtra) prophylaxis in preventing venous thromboembolism following major orthopaedic surgery. J Thromb Haemost 2003; 1:383–384 28 Flordal PA, Bergqvist D, Ljungstrom KG, et al. Clinical relevance of the fibrinogen uptake test in patients having general abdominal surgery: relation to major thromboembolism and mortality. Thromb Res 1995; 80:491– 497 29 Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996; 348:224–228 CHEST / 124 / 6 / DECEMBER, 2003 SUPPLEMENT
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30 Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery: results of a double-blind, prospective, randomized, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997; 77:26 –31 31 Cogo A, Bernardi E, Prandoni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994; 154:164 –167 32 Morganthaler TI, Ryu JH. Clinical characteristics of fatal pulmonary embolism in a referral hospital. Mayo Clin Proc 1995; 70:417– 424 33 Rasmussen MS, Wille-Jorgensen P, Jorgensen LN. Postoperative fatal pulmonary embolism in a general surgical department. Am J Surg 1995; 169:214 –216 34 Bergqvist D, Lindblad B. A 30 year survey of pulmonary embolism verified at autopsy: an analysis of 1274 surgical patients. Br J Surg 1985; 72:105–108 35 Douketis JD, Eikelboom JW, Quinlan DJ, et al. Shortduration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 2002; 162:1465–1471 36 Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison; North American Fragmin Trial Investigators. Arch Intern Med 2000; 160:2208 –2215 37 Ricotta S, Iorio A, Parise P, et al. Post discharge clinically overt venous thromboembolism in orthopaedic surgery patients with negative venography: an overview analysis. Thromb Haemost 1996; 76:887– 892 38 Robinson KS, Anderson DR, Gross M, et al. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty: the Post-Arthoplasty Screening Study; a randomized, controlled trial. Ann Intern Med 1997; 127:439 – 445 39 Leclerc JR, Gent M, Hirsh J, et al. The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin. Arch Intern Med 1998; 158:873– 878 40 Colwell CW Jr, Collis DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty: evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am 1999; 81:932–940 41 Heit JA, Elliott CG, Trowbridge AA, et al. Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 132:853– 861 42 O’Donnell M, Linkins L, Kearon C, et al. Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low molecular weight heparin following elective hip arthroplasty: a systematic re-
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view. Arch Intern Med 2003; 163:1362–1366 43 Bergqvist D, Benoni G, Bjo¨ rgell O, et al. Low-molecularweight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335:696 –700 44 Lassen MR, Borris LC, Anderson BS, et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty: the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998; 89:281–287 45 Haentjens P. Venous thromboembolism after total hip arthroplasty: a review of incidence and prevention during hospitalization and after hospital discharge. Acta Orthop Belg 2000; 66:1– 8 46 Manganelli D, Pazzagli M, Mazzantini D, et al. Prolonged prophylaxis with unfractioned heparin is effective to reduce delayed deep vein thrombosis in total hip replacement. Respiration 1998; 65:369 –374 47 Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001; 358:9 –15 48 Bergqvist D, Agnelli G, Cohen AF, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346:975–980 49 Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340:901–907 50 Schulman S, Granqvist S, Holmstro¨ m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336:393–398 51 Turpie AG, Bauer KA, Eriksson BI, et al. 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; 162:1833–1840 52 Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003; 163:1337–1342 53 Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S–121S 54 Ginsberg JS, Turkstra F, Buller HR, et al. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med 2000; 160:669 – 672 55 Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332:1661–1665 56 Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103:2453–2460
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
Venous thromboembolism (VTE) prophylaxis is indicated while in the hospital after major surgery. There is evidence that the prevalence of asymptomatic deepvein thrombosis, detected by routine venography after major orthopedic surgery, is lower at hospital discharge in patients who have received 10 days rather than 5 days of prophylaxis. This observation supports the current American College of Chest Physicians (ACCP) recommendation for a minimum of 7 to 10 days of prophylaxis after hip and knee replacement, even if patients are discharged from the hospital within 7 days of surgery. As risk of VTE persists for up to 3 months after surgery, patients at high risk for postoperative VTE may benefit from extended prophylaxis (eg, an additional 3 weeks after the first 7 to 10 days). Extended prophylaxis with low-molecular-weight heparin (LMWH) reduces the frequency of postdischarge VTE by approximately two thirds after hip replacement; however, the resultant absolute reduction in the frequency of fatal pulmonary embolism is small (ie, estimated at 1 per 2,500 patients). Indirect evidence suggests that, compared with LMWH, efficacy of extended prophylaxis after hip replacement is greater with fondaparinux, similar with warfarin, and less with aspirin. Extended prophylaxis is expected to be of less benefit after knee than after hip replacement. In keeping with current ACCP recommendations, at a minimum, extended prophylaxis should be used after major orthopedic surgery in patients who have additional risk factors for VTE (eg, previous VTE, cancer). If anticoagulant drug therapy is stopped after 7 to 10 days, an additional month of prophylaxis with aspirin should be considered. (CHEST 2003; 124:386S–392S) Key words: aspirin; deep vein thrombosis; heparin; low-molecular-weight heparin; prophylaxis; surgery venous thromboembolism; warfarin Abbreviations: ACCP ⫽ American College of Chest Physicians; DVT ⫽ deep vein thrombosis; INR ⫽ international normalized ratio; LMWH ⫽ low-molecular-weight heparin; PE ⫽ pulmonary embolism; VTE ⫽ venous thromboembolism *From the McMaster Clinic, Henderson General Hospital, Hamilton, ON, Canada. Dr. Kearon is supported by a Research Scholarship from the Heart and Stroke Foundation of Canada, and he has received an honorarium from the American College of Chest Physicians for the preparation of this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Clive Kearon, MD, McMaster Clinic, 70 Wing, Henderson General Hospital, 711 Concession St, Hamilton, ON, L8V 1C3 Canada; e-mail: [email protected] 386S
thromboembolism (VTE), which includes deep V enous vein thrombosis (DVT) and pulmonary embolism (PE), is an important complication of major surgery. Postoperative VTE can be prevented using pharmacologic and mechanical methods; by avoiding the need to treat patients who acquire nonfatal DVT and PE, prophylaxis reduces costs1,2 as well as saves lives.3–5 Based on assessment of patient-related and surgical factors, individual risk of postoperative VTE can be stratified as low, moderate, or high.6,7 There is widespread agreement that patients who are at moderate or high risk for postoperative VTE should receive prophylaxis while in the hospital.6 It has been proposed that patients with a high risk of postoperative VTE should also receive prophylaxis after they leave the hospital. However, it is uncertain which high-risk patients should receive postdischarge prophylaxis, which method of prophylaxis should be used, and for how long prophylaxis should be continued after leaving the hospital. This review describes the natural history of postoperative VTE, evaluates evidence relating to the use of various methods and durations of prophylaxis in different groups of high-risk surgical patients, and makes recommendations about the use of prophylaxis after hospital discharge. It focuses primarily on patients who have had major hip or knee surgery, as these patients have been well studied and are thought to have the most to gain from extended prophylaxis.6
Natural History and Epidemiology of Postoperative VTE Elements of the natural history and epidemiology of postoperative VTE that may influence decisions about the use and duration of prophylaxis after surgery are summarized in Table 1.7–37 General conclusions that can be drawn from this evidence include the following: (1) the risk of VTE differs with the type of surgery and among patients: patients with a high risk for postoperative VTE can be identified before they have surgery; (2) the risk of VTE is highest soon after surgery: prophylaxis while in the hospital prevents more thromboembolic events than prophylaxis after leaving the hospital; (3) the time course for development of postoperative VTE may differ with the type of surgery: a risk of VTE that remains high for a long time after a particular type of surgery favors more prolonged prophylaxis; and (4) the greater the number of days of postoperative prophylaxis, the lower the prevalence of asymptomatic DVT when prophylaxis is stopped: a minimum duration of prophylaxis may be indicated after high-risk surgery.
Frequency of Symptomatic VTE After Major Orthopedic Surgery in Patients Who Receive Recommended Prophylaxis for 7 to 10 Days The American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy currently recommends use of low-molecular-weight heparin (LMWH) or warfarin (target international normalized ratio [INR], 2.0 to 3.0) for at least 7 to 10 days after
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
Table 1—Natural History and Epidemiology of Postoperative VTE Half of symptomatic VTEs occur in patients who are in the hospital or a nursing home (approximately 40%), or within 3 months of leaving the hospital (approximately 10%).7,8 Half of hospital-associated VTEs occur in surgical, and half occur in nonsurgical patients.7,8 Surgical risk factors for VTE include complexity of surgery,9 general vs regional anesthesia,10,11 and associated venous trauma.12 Patient risk factors for VTE include previous VTE,13,14 cancer,10,13 estrogen therapy including tamoxifen,15,16 thrombophilia,13,17 obesity,10,13,14 advanced age,10,13,14,18 poor mobilization,13,14 and female gender.14,18,19 Major orthopedic surgery is associated with approximately twice as high a risk of VTE as general surgery.4,18,20 Postoperative DVT usually starts in the calf or, less commonly, at the site of venous trauma.12,21–23 Three fourths of DVT that occur after major orthopedic surgery are in the operated leg.23,24 A large proportion (perhaps one half) of DVTs that are associated with surgery start intraoperatively, and many of these resolve spontaneously (approximately half within 72 h).21,25,26 Use of prophylaxis after surgery facilitates spontaneous lysis of perioperative thrombi and prevents new thrombi from starting. For example, compared to those who received ⱕ 5 d of LMWH or fondaparinux after hip or knee replacement, the proportion of patients with venographically detected DVT at hospital discharge decreased by 22% with 6 to 8 d, and by 34% with 9 to 11 d of prophylaxis.27 The risk of progression of postoperative venous thrombosis appears to be greater if the initial thrombosis is large, and if there are continuing risk factors for thrombosis (eg, immobilization).21,26,28 The risk of symptomatic VTE is generally highest within 2 wk of surgery, and remains elevated for about 2 to 3 mo.3,5,18,29–31 Without prophylaxis, the highest risk period for fatal postoperative PE appears to be approximately 3 to 7 d following surgery.3,5,32–34 Risk of VTE drops more rapidly after knee replacement than after hip replacement.18,35 Among hip and knee replacement patients who receive prophylaxis while in the hospital: (1) The frequency of venographically detected (asymptomatic) DVT at hospital discharge is twice as high after knee than after hip replacement (eg, all DVT, 39% vs 16%; proximal DVT, 8% vs 4%35); (2) The frequency of symptomatic VTE while in the hospital is similar after knee and hip replacement (eg, prospective studies: knees 1.3% vs hips 1.0%35; retrospective epidemiological study: knees 1.1% vs hips 0.7%18); (3) The frequency of symptomatic DVT or PE after hospital discharge is higher after hip than after knee replacement (eg, clinical trials: hips 2.5% vs knees 1.4%35; retrospective epidemiologic study: hips 2.1% vs knees 1.0%)18; (4) Among patients who received prophylaxis, median time to occurrence of symptomatic DVT was 7 d after knee replacement and 17 d after hip replacement.18 Of hip replacement patients without DVT at hospital discharge (normal venogram) who do not continue prophylaxis, approximately 15% have DVT on venography that is performed 3 wk later, and approximately one third of these are proximal.29,30,36 Absence of DVT on venography at hospital discharge approximately 11 d after major orthopedic surgery was associated with a subsequent risk of symptomatic VTE of 1.3% (30 of 2,361 patients) during 8 wk of follow-up in patients who stop prophylaxis (studies from early 1990s).37 Symptomatic VTE is approximately 50% higher after fractured hip surgery (average age, 79 yr) than after hip or knee replacement (average age, 67 yr).5
elective hip or knee replacement, or surgery for hip fracture.6 A minimum of 7 to 10 days is recommended because this was the duration of prophylaxis that was administered before leaving the hospital in studies6,35 that established the efficacy of LMWH and warfarin after major orthopedic surgery. Length of hospital stay after hip or knee replacement has decreased during the last 10 years, and now many patients are discharged from the hospital on, or before, the fifth postoperative day (see the article by F.A. Anderson in this supplement). In order to receive the minimum recommended duration of prophylaxis of 7 to 10 days, these patients need to receive additional days of prophylaxis with LMWH or warfarin after hospital discharge. In order to decide if prophylaxis is warranted after the initial 7 to 10 days, it is important to know the expected frequency of VTE after orthopedic surgery if prophylaxis is not extended. This frequency can be estimated from prospective studies and from a large epidemiologic study.
symptomatic VTE within 3 months of surgery in a total of 6,089 patients who had undergone hip (approximately 4,500) or knee (approximately 1,500) replacement and received LMWH40 – 42 or warfarin38 – 41 for 7 to 10 days. Predischarge screening to detect asymptomatic DVT or PE was not performed in these studies, thereby avoiding the possibility that the results of such tests could have led to overdiagnosis of asymptomatic VTE or, conversely, that treatment of asymptomatic VTE could have reduced the subsequent frequency of symptomatic VTE.42 The overall frequency of symptomatic VTE within 3 months of surgery was 3.2%; 1.1% occurred while receiving prophylaxis in the hospital and 2.2% occurred during about 80 days of follow-up after stopping prophylaxis and leaving the hospital.35 Confirmed fatal PE occurred in 0.1% of patients: 0.04% while in the hospital and 0.06% after leaving the hospital.35
Prospective Studies
In a study of linked hospital records by White and colleagues,18 2.4% of patients who had undergone hip (20,000 patients) or knee (24,000 patients) replacement had a symptomatic VTE within 3 months of surgery; 0.9%
Douketis and colleagues35 analyzed data from four prospective studies38 – 41 that assessed the frequency of www.chestjournal.org
Retrospective Epidemiologic Study
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occurred while in the hospital, and 1.5% occurred after leaving the hospital.18 Eighty-eight percent of inpatients and 32% of outpatients were estimated to have received prophylaxis.18 Differences in Risk and Timing of Symptomatic VTE After Hip and After Knee Surgery: There is convincing evidence that the timing of VTE differs after hip and knee surgery (Table 1). In the early postoperative period, knee replacement is associated with at least as high a risk of symptomatic VTE as hip surgery (prospective studies35: knees, 1.3%; hips, 1.0%; epidemiologic study18: knees, 1.1%, hips, 0.7%). However, the risk of symptomatic VTE after hospital discharge is close to twice as great after hip replacement (prospective studies35: hip, 2.5%, knees, 1.4%; epidemiologic study18: hips, 2.1%, knees, 1.0%). Frequency of Symptomatic VTE After Leaving Hospital: Based on the above data, the following are reasonable estimates for the expected frequency of different presentations of symptomatic VTE within 80 days of hospital discharge if LMWH or warfarin therapy is stopped after 7 to 10 days: hip replacement–symptomatic DVT or PE, approximately 2.4%; symptomatic nonfatal PE, approximately 0.6%; fatal PE, approximately 0.06% (Table 2); knee replacement–symptomatic DVT or PE, approximately 1.4%; symptomatic nonfatal PE, approximately 0.4%; fatal PE, approximately 0.04%.
Efficacy and Safety of Different Methods of Extended Prophylaxis After Major Orthopedic Surgery LMWH The efficacy and safety of extended prophylaxis with LMWH has been evaluated after hip and knee replacement in eight controlled studies.24,29,30,36,41,43– 45 The findings of these studies, and of a study46 evaluating extended prophylaxis with unfractionated heparin, have been combined in a meta-analysis by Eikelboom and colleagues.47 Extended prophylaxis reduced the frequency of asymptomatic DVT by 51% (from 19.6 to 9.6%), symptomatic VTE by 62% (from 3.3 to 1.3%), and symptomatic PE by 57% (0.62 to 0.15%).47 It is possible that the frequency of symptomatic VTE reported by many of these studies was
influenced by the results of tests that were performed to screen for asymptomatic VTE. In an analysis of these studies that was designed to avoid this possibility, O’Donnell and colleagues42 found a lower absolute, but a similar proportional, risk reduction with extended prophylaxis after hip replacement. A reasonable estimate, therefore, is that an additional 3 weeks of LMWH therapy after the first 7 to 10 days of prophylaxis will reduce the frequency of symptomatic VTE by close to two thirds after major orthopedic surgery (Table 2). However, knee replacements accounted for less than one third of patients in these studies, and as extended LMWH appears to be less effective among those who had a knee replacement (risk reduction: 26% for symptomatic VTE, and 16% for asymptomatic DVT47), the efficacy of extended prophylaxis after knee replacement is uncertain. Provided patients with contraindications are not treated, extended prophylaxis with LMWH does not appear to be associated with increased major bleeding after orthopedic surgery, although minor bleeding is approximately 50% more common (3.4% vs 2.7%).47 Extended prophylaxis with LMWH has also been shown to reduce the frequency of VTE by approximately two thirds after surgery for cancer; the frequency of asymptomatic and symptomatic VTE in these patients was lower than after orthopedic surgery.48
Warfarin Although warfarin (target INR, 2.0 to 3.0) is widely used for extended prophylaxis after orthopedic surgery (see the article by F. A. Anderson in this supplement), to my knowledge there are no controlled studies evaluating warfarin in this setting. Warfarin appears to be less effective and associated with less bleeding than LMWH within a week of hip or knee replacement,6,40 both of which may be explained by the delayed onset of anticoagulation with warfarin. However, three sources of evidence suggest that warfarin is likely to have a similar efficacy to LMWH for extended prophylaxis. First, 7 to 10 days of warfarin therapy appears to be associated with a similar frequency of symptomatic VTE within 3 months of hip and knee replacement as 7 to 10 days of LMWH.6,40 Second, warfarin is very effective for the secondary prevention of VTE.49,50 Third, in a large casecontrol study,14 use of warfarin after hospital discharge was associated with an odds ratio of 0.6 for hospital readmission
Table 2—Postdischarge Frequency of Symptomatic VTE per 10,000 Hip Replacements (Number Needed to Treat to Prevent One Event)* Extended Prophylaxis Event
Control
DVT/PE PE Fatal PE
240 60 6
Aspirin 160 (125)† 40 (500)† 4 (5,000)†
LMWH/Warfarin
Pentasaccharide
80 (62) 20 (250) 2 (2,500)
24 (46) 6 (185) 0.6 (1,850)
*Postdischarge frequency of symptomatic VTE, 2.4%; PE, 0.6%; and fatal PE, 0.06%. Risk reduction is for VTE of one third (0.33%) for aspirin, two thirds (0.67%) for LMWH/warfarin, and nine tenths (90%) for fondaparinux. †Number needed to treat with aspirin compared to no extended prophylaxis (control) to prevent one symptomatic VTE event is the same as the number needed to treat with LMWH/warfarin compared to aspirin. 388S
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
with symptomatic VTE after hip replacement. Given that recent surgery is a risk factor for anticoagulant-induced bleeding, it is probable that extended prophylaxis with warfarin is associated with an increase in major bleeding51; however, it is not known how this risk compares with other antithrombotic agents that may be used in this setting.
Aspirin Aspirin is not recommended for prevention of VTE during the first 7 to 10 days after orthopedic surgery, as there are more effective methods available, such as LMWH and warfarin.6 Although aspirin is also likely to be less effective than LMWH and warfarin for extended prophylaxis, it has the advantages of simplicity, low cost, and safety. In the Pulmonary Embolism Prevention trial5 which included 13,000 patients with hip fracture and 4,000 patients with hip or knee replacement, aspirin reduced the risk of symptomatic VTE by 36%, and fatal PE by 53%. This effect persisted over the 35 days of aspirin use. These findings are consistent with the results of the Antiplatelet Trialists’ Collaboration,20 in which antiplatelet therapy reduced postoperative DVT by 26% and PE by 63% in an overview of 60 studies. Therefore, a reasonable estimate is that, following an initial 7 to 10 days of LMWH or warfarin therapy, a month of aspirin therapy (81 to 325 mg/d) will reduce the frequency of postdischarge symptomatic VTE by one third (Table 2). Aspirin was associated with an increase in minor GI bleeding in the Pulmonary Embolism Prevention trial5 (absolute increase of 0.9%).
Graduated Compression Stockings Although graduated compression stockings substantially reduce the frequency of leg scanning-detected DVT after general surgery, they are of uncertain, or little, benefit after hip or knee replacement.6 Graduated compression stockings cannot be recommended as a method of extended prophylaxis after orthopedic surgery.
Fondaparinux (Synthetic Pentasaccharide) Fondaparinux has been shown to be more effective than LMWH for the first 7 to 10 days of prophylaxis after major orthopedic surgery, but was associated with a small additional risk of bleeding that was attributable to administering the first dose ⬍ 6 h after surgery.51 A recently completed placebo-controlled study52 showed that extended prophylaxis with fondaparinux after hip fracture surgery reduced the frequency of asymptomatic DVT by 96% and symptomatic VTE by 89% (from 2.7% to 0.3%). Extended prophylaxis with fondaparinux was associated with a tendency to increased bleeding compared to placebo bleeding (major bleeding, 2.4% vs 0.6%).52
Improving the Risk/Benefit Ratio of Extended Prophylaxis The main risk associated with extended-prophylaxis is bleeding, and the main benefit is prevention of VTE. Therefore, the risk/benefit ratio of extended prophylaxis improves if a greater number of episodes of VTE are prevented and/or fewer bleeds are caused. www.chestjournal.org
Preventing More Episodes of VTE Assuming that the proportional risk reduction does not decline, the absolute reduction in number of episodes of VTE achieved by extended prophylaxis increased with the patients risk of VTE. Consistent with this concept, the ACCP recommends that, at a minimum, patients with a high risk of VTE after hip or knee replacement should receive extended prophylaxis.6 Previous VTE and active malignancy are the most potent risk factors for postoperative VTE.7,10,14 Tamoxifen and hormonal replacement therapy also appear to substantially increase the risk of postoperative VTE, and withdrawing treatment with these agents for a month before and after surgery is expected to reduce this risk.15,16 Advanced age,7,10,14,18 obesity,7,10,14 poor mobilization,7,14 and female gender14,18,19 are less potent risk factors for VTE.
Avoiding Bleeding Presence of risk factors for bleeding argues against use of extended prophylaxis. Concern about bleeding at the surgical site is expected to be the most important risk factor for bleeding. Others include previous GI bleeding, poor control of warfarin therapy, or renal failure.35 The influence of risk factors for VTE and/or bleeding on choice of extended prophylaxis is summarized in Table 3.
Benefit to Preventing Asymptomatic DVT Most DVTs that occur after surgery do not progress to cause symptomatic DVT or PE. For example, using the estimates previously presented for patients who receive 7 to 10 days of LMWH therapy, the ratio of asymptomatic DVT at hospital discharge to development of symptomatic VTE within the next 3 months is about 6:1 for hip replacement and 28:1 for knee replacement. The clinical importance of asymptomatic isolated calf and proximal DVTs that, in the short term, do not progress to symptomatic DVT or symptomatic PE is uncertain. Such thrombi could increase the long-term risk of symptomatic VTE or could cause the postthrombotic syndrome. Ginsberg and colleagues54 compared the prevalence of the postthrombotic syndrome among patients who had no DVT (164 patients), asymptomatic calf DVT (66 patients), or asymptomatic proximal DVT (75 patients) on venograms performed at hospital discharge after major orthopedic surgery. Patients who were found to have DVT at venography had been treated with anticoagulant therapy for up to 3 months. An average of 5 years later, prevalence of the postthrombotic syndrome was 4% in those without DVT, 6% in those with isolated calf DVT, and 4% in those with proximal DVT, suggesting that treated asymptomatic DVTs rarely cause the postthrombotic syndrome. However, it is uncertain if this is also true for asymptomatic DVTs that are not treated. It is not known if untreated asymptomatic postoperative DVTs predispose to symptomatic VTE years later. As treated symptomatic postoperative DVTs, particularly if confined to the calf, are associated with a low risk of recurrence,55,56 it is unlikely that asymptomatic DVTs predispose to remote episodes of VTE. CHEST / 124 / 6 / DECEMBER, 2003 SUPPLEMENT
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Table 3—Factors Influencing Use and Method of Extended Prophylaxis After Major Orthopedic Surgery* Variables Risk factors for VTE Previous VTE Cancer (active) Tamoxifen or estrogen therapy† Hip vs knee surgery Known thrombophilia Slow mobilization or obesity Risk factors for bleeding Uncertain surgical site hemostasis Previous GI bleeding Cost concerns Difficulty with injections Poor access to INR monitoring Poor patient compliance Patient preference
Fondaparinux
LMWH
Warfarin
Aspirin
None
⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹
⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹
⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹
⫹ ⫹ ⫹ ⫹ ⫹ ⫹
⫺⫺ ⫺⫺ ⫺⫺
⫺⫺ ⫺ ⫹⫹ ⫺⫺
⫺⫺ ⫺ ⫹⫹ ⫺⫺
⫺⫺ ⫺ ⫹
⫺ ⫺
⫺
⫹/⫺
⫹/⫺
⫹/⫺
⫹/⫺
⫺⫺ ⫺⫺ ⫹/⫺
⫺⫺
⫺
*⫹⫹⫹ ⫽ strongly favors; ⫹⫹ ⫽ moderately favors; ⫹ ⫽ weakly favors; ⫺ ⫽ weakly discourages; ⫺⫺ ⫽ moderately discourages; no symbol ⫽ neutral influence. †Consider withholding tamoxifen or estrogen therapy for 1 month before and after surgery.
Recommended Duration of Prophylaxis After Major Orthopedic Surgery The Sixth ACCP Consensus Conference on Antithrombotic Therapy,6 which was published in January 2001, makes two main recommendations about the duration of anticoagulant prophylaxis after major orthopedic surgery. The first recommendation, which relates to the minimum duration of initial prophylaxis with LMWH or warfarin (target INR, 2.5; range, 2.0 to 3.0) is as follows: “The optimal duration of anticoagulant prophylaxis after total hip or knee replacement surgery is uncertain, although at least 7 to 10 days of prophylaxis is recommended (grade 1A).” The second recommendation, which relates to the use of extended prophylaxis, is as follows: “Extended out-of-hospital LMWH prophylaxis (beyond 7 to 10 days after surgery) may reduce the incidence of clinically important thromboembolic events, and we recommend this approach at least for high-risk patients (grade 2A because of uncertainty regarding cost-effectiveness).” Both of these recommendations still appear to be valid; however, both are open to interpretation. In the remainder of this review, I will suggest approaches to the implementation of these recommendations that reflect my interpretation of current evidence and consider differences among patients and between surgical centers.
Method of Initial Prophylaxis In the absence of a contraindication, anticoagulant therapy is the preferred method of initial prophylaxis after hip or knee replacement or surgery for hip fracture; fondaparinux may be added to LMWH and warfarin as appropriate options. Aspirin is not an adequate initial method of prophylaxis.
Duration of Initial Prophylaxis Anticoagulant prophylaxis should be used for a minimum of 7 days, and 10 days is expected to be superior. This usually 390S
requires that prophylaxis is continued for some days after hospital discharge. A minimum of 10 days rather than 7 days of prophylaxis should be considered if there is a delay (eg, ⬎ 24 h) between surgery and when LMWH or fondaparinux therapy is started, or if warfarin is used. Anticoagulant prophylaxis should also be continued while in the hospital, even if hospital discharge is markedly delayed.
Method of Extended Prophylaxis Based on indirect comparisons, fondaparinux is expected to be more effective than LMWH but may be associated with more bleeding. LMWH therapy reduces the frequency of symptomatic VTE substantially, without causing an increase of major bleeding. Warfarin is expected to be as effective as LMWH but may cause more bleeding during extended prophylaxis. If the decision has been made not to continue fondaparinux, LMWH, or warfarin therapy beyond 7 to 10 days, switching to aspirin for a month of extended prophylaxis is recommended (unless there is a contraindication). The decision to use extended prophylaxis with fondaparinux, LMWH, warfarin, or aspirin, or not to use any form of extended prophylaxis, is influenced by many factors that are summarized in Table 3. Currently, our practice is to extend anticoagulant prophylaxis to 4 weeks after hip or knee replacement or hip fracture if patients have a particularly high risk of VTE, as evidenced by a previous VTE or active malignancy (often a pathologic hip fracture), provided they do not have a high risk of bleeding. This selective approach to the use of extended anticoagulant prophylaxis is considered conservative by many; a more liberal approach, including use of such prophylaxis in all major orthopedic patients who are not at high risk for bleeding, is also reasonable. If we do not extend anticoagulant prophylaxis, we routinely recommend aspirin (80 mg/d or 325 mg/d) for a month after completing 7 to 10 days of initial prophylaxis with anticoagulants. We do not use
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents
aspirin if there are concerns about aspirin intolerance or if there is a history of GI bleeding.
Duration of Extended Prophylaxis The longer that prophylaxis is administered, the more effective it is expected to be. Whereas the decision is usually to stop at 7 to 10 days, or to continue prophylaxis for approximately 4 weeks, these two options should not be applied rigidly. Extended prophylaxis for ⬍ 4 weeks is expected to be more effective than stopping at 10 days and may be appropriate for some patients (eg, out-of-hospital prophylaxis is poorly tolerated). Longer than 4 weeks of prophylaxis may be indicated for discharged patients who remain at high risk for VTE (eg, very immobile with additional risk factors).
Standardized Approach to Initial and Extended Prophylaxis at Individual Hospitals Decisions about VTE prophylaxis are influenced by, and impact on, a large number of health-care providers, including surgeons, anesthesiologists, anticoagulation services, nurses, community services, family doctors, pharmacists, and hospital administration, as well as patients and their families. While it is important that there is the flexibility to tailor management in individual patients, in order to avoid confusion and ensure that all patients receive appropriate prophylaxis, provision of prophylaxis should be standardized as much as possible within each hospital. This requires close communication and cooperation among all parties.
References 1 Salzman EW, Davies GC. Prophylaxis of venous thromboembolism: analysis of cost effectiveness. Ann Surg 1980; 191:207–218 2 Drummond M, Aristides M, Davies L, et al. Economic evaluation of standard heparin and enoxaparin for prophylaxis against deep vein thrombosis in elective hip surgery. Br J Surg 1994; 81:1742–1746 3 Kakkar VV, Corrigan TP, Fossard DP. Prevention of fatal postoperative pulmonary embolism by low doses of heparin: an international multicentre trial. Lancet 1975; 2:45–51 4 Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988; 318:1162–1173 5 Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355:1295–1302 6 Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119:132S–175S 7 Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000; 83:657– 660 8 Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162:1245–1248 9 Field ES, Nicolaides AN, Kakkar VV, et al. Deep vein thrombosis in patients with fractures of the femoral neck. Br J Surg 1972; 59:377 10 Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip www.chestjournal.org
replacement. N Engl J Med 1997; 337:1329 –1335 11 Modig J, Hjelmstedt A, Sahlstedt B, et al. Comparative influences of epidural and general anesthesia on deep venous thrombosis in pulmonary embolism after total hip replacement. Acta Chir Scand 1981; 147:125–130 12 Stamatakis JD, Kakkar V, Sagar S, et al. Femoral vein thrombosis and total hip replacement. BMJ 1977; 2:223–225 13 Kearon C. Natural history of venous thromboembolism. Semin Vasc Med 2001; 1:27–37 14 White RH, Gettner S, Newman JM, et al. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med 2000; 343:1758 –1764 15 Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132:689 – 696 16 Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131–2139 17 Svensson PJ, Benoni G, Fredin H, et al. Female gender and resistance to activated protein C (FV:Q506) as potential risk factors for thrombosis after elective hip arthroplasty. Thromb Haemost 1997; 78:993–996 18 White RH, Romano PS, Zhou H, et al. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998; 158:1525–1531 19 Eriksson BI, Ekman S, Ka¨ lebo P, et al. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347:635– 639 20 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994; 308:235–246 21 Kakkar VV, Howe CT, Flanc C, et al. Natural history of postoperative deep-vein thrombosis. Lancet 1969; 2:230 –232 22 Nicolaides AN, Kakkar VV, Field ES, et al. The origin of deep vein thrombosis: a venographic study. Br J Radiol 1971; 44:653– 663 23 Cruickshank MK, Levine MN, Hirsh J, et al. An evaluation of impedance plethysmography and 125I-fibrinogen leg scanning in patients following hip surgery. Thromb Haemost 1989; 62:830 – 834 24 Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement: Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001; 83:336 –345 25 Flanc C, Kakkar VV, Clarke MB. The detection of venous thrombosis of the legs using 125-I fibrinogen. Br J Surg 1968; 55:742–747 26 Maynard MJ, Sculco TP, Ghelman B. Progression and regression of deep vein thrombosis after total knee arthroplasty. Clin Orthop 1991; 273:125–130 27 Eriksson BI, Bauer KA, Lassen MR, et al. Influence of the duration of fondaparinux (Arixtra) prophylaxis in preventing venous thromboembolism following major orthopaedic surgery. J Thromb Haemost 2003; 1:383–384 28 Flordal PA, Bergqvist D, Ljungstrom KG, et al. Clinical relevance of the fibrinogen uptake test in patients having general abdominal surgery: relation to major thromboembolism and mortality. Thromb Res 1995; 80:491– 497 29 Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996; 348:224–228 CHEST / 124 / 6 / DECEMBER, 2003 SUPPLEMENT
391S
30 Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery: results of a double-blind, prospective, randomized, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997; 77:26 –31 31 Cogo A, Bernardi E, Prandoni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994; 154:164 –167 32 Morganthaler TI, Ryu JH. Clinical characteristics of fatal pulmonary embolism in a referral hospital. Mayo Clin Proc 1995; 70:417– 424 33 Rasmussen MS, Wille-Jorgensen P, Jorgensen LN. Postoperative fatal pulmonary embolism in a general surgical department. Am J Surg 1995; 169:214 –216 34 Bergqvist D, Lindblad B. A 30 year survey of pulmonary embolism verified at autopsy: an analysis of 1274 surgical patients. Br J Surg 1985; 72:105–108 35 Douketis JD, Eikelboom JW, Quinlan DJ, et al. Shortduration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 2002; 162:1465–1471 36 Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison; North American Fragmin Trial Investigators. Arch Intern Med 2000; 160:2208 –2215 37 Ricotta S, Iorio A, Parise P, et al. Post discharge clinically overt venous thromboembolism in orthopaedic surgery patients with negative venography: an overview analysis. Thromb Haemost 1996; 76:887– 892 38 Robinson KS, Anderson DR, Gross M, et al. Ultrasonographic screening before hospital discharge for deep venous thrombosis after arthroplasty: the Post-Arthoplasty Screening Study; a randomized, controlled trial. Ann Intern Med 1997; 127:439 – 445 39 Leclerc JR, Gent M, Hirsh J, et al. The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin. Arch Intern Med 1998; 158:873– 878 40 Colwell CW Jr, Collis DK, Paulson R, et al. Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty: evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am 1999; 81:932–940 41 Heit JA, Elliott CG, Trowbridge AA, et al. Ardeparin sodium for extended out-of-hospital prophylaxis against venous thromboembolism after total hip or knee replacement: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 132:853– 861 42 O’Donnell M, Linkins L, Kearon C, et al. Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low molecular weight heparin following elective hip arthroplasty: a systematic re-
392S
view. Arch Intern Med 2003; 163:1362–1366 43 Bergqvist D, Benoni G, Bjo¨ rgell O, et al. Low-molecularweight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335:696 –700 44 Lassen MR, Borris LC, Anderson BS, et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty: the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998; 89:281–287 45 Haentjens P. Venous thromboembolism after total hip arthroplasty: a review of incidence and prevention during hospitalization and after hospital discharge. Acta Orthop Belg 2000; 66:1– 8 46 Manganelli D, Pazzagli M, Mazzantini D, et al. Prolonged prophylaxis with unfractioned heparin is effective to reduce delayed deep vein thrombosis in total hip replacement. Respiration 1998; 65:369 –374 47 Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001; 358:9 –15 48 Bergqvist D, Agnelli G, Cohen AF, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346:975–980 49 Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340:901–907 50 Schulman S, Granqvist S, Holmstro¨ m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997; 336:393–398 51 Turpie AG, Bauer KA, Eriksson BI, et al. 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; 162:1833–1840 52 Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003; 163:1337–1342 53 Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S–121S 54 Ginsberg JS, Turkstra F, Buller HR, et al. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med 2000; 160:669 – 672 55 Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332:1661–1665 56 Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103:2453–2460
Contemporary Issues in DVT Prophylaxis: Review of Old, New, and Innovative Agents