(Chest. 2005;128:3364-3371.)
© 2005
American College of Chest Physicians
Identifying Orthopedic Patients at High Risk for Venous Thromboembolism Despite Thromboprophylaxis*
Renée L. Schiff, MD;
Susan R. Kahn, MD, MSc;
Ian Shrier, MD, PhD;
Carla Strulovitch, RN;
Wahbi Hammouda, MD;
Eva Cohen, BPharm, DPH and
David Zukor, MD
* Department of Medicine (Drs. Schiff and Kahn), McGill University; and Center for Clinical Epidemiology and Community Studies (Dr. Kahn, Dr. Shrier, and Ms. Strulovitch), Division of Orthopedic Surgery (Dr. Zukor), Division of Hematology (Dr. Hammouda), and Department of Pharmacy (Ms. Cohen), SMBD Jewish General Hospital, Montreal, QC, Canada.
Correspondence to: Susan R. Kahn, MD, MSc, Center for Clinical Epidemiology and Community Studies, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste. Catherine Rm. A-127, Montreal, Quebec H3T 1E2; e-mail: susan.kahn{at}mcgill.ca
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Abstract
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Objective: To evaluate risk factors for venous thromboembolism (VTE) despite thromboprophylaxis in major orthopedic surgery patients at a tertiary care hospital.
Methods: Charts from consecutive patients who underwent total hip replacement (THR), total knee replacement (TKR), or hip fracture surgery (HFS) [hip pinning or hemiarthroplasty] from August 1, 1999, to April 30, 2000, at a large Canadian teaching hospital were abstracted using standardized case report forms. Data were collected on patient characteristics, surgical characteristics, and thromboprophylaxis regimen. Results of tests performed for suspected VTE were documented. Associations between characteristics of interest and objectively confirmed VTE were examined in multivariate analysis.
Results: Over the study period, 310 patients underwent major orthopedic surgery and received standard thromboprophylaxis with either dalteparin or enoxaparin (mean duration of prophylaxis, 7 days). Of these, 34% underwent THR, 30% underwent TKR, and 36% underwent HFS. Of 83 suspected cases of VTE, 44 cases (7 proximal and 37 distal deep venous thrombosis [DVT]); 14% of study population) were confirmed with objective testing. Multivariate analyses revealed that knee surgery (odds ratio [OR], 4.8; 95% confidence interval [CI], 2.3 to 10.1) and type of low molecular weight heparin (LMWH) [enoxaparin (more protective): OR, 0.39; 95% CI, 0.20 to 0.80] independently predicted VTE. No patient characteristics (including previous VTE, malignancy, hormonal therapy, postoperative complications) were associated with VTE.
Conclusion: Despite standard thromboprophylaxis, symptomatic breakthrough VTE, primarily distal DVT, developed in 14% of patients undergoing major orthopedic surgery. Factors that independently predicted VTE in our population were TKR surgery and type of LMWH. TKR patients may warrant more aggressive postoperative physiotherapy and ambulation and adjunctive prophylactic measures such as pneumatic compression. Due to the heterogeneity of different LMWH compounds, direct comparison of the effectiveness of enoxaparin with dalteparin for orthopedic prophylaxis in prospective, randomized trials seems warranted.
Key Words: deep venous thrombosis • low-molecular-weight heparin • orthopedic surgery • thromboprophylaxis • venous thromboembolism
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Introduction
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It is widely recognized that orthopedic surgery is associated with a very high rate of postoperative venous thromboembolism (VTE). Contributing factors include direct vessel trauma, venous stasis of the limb, and a population that is already at high baseline risk of VTE due to age and immobility.1 In the absence of thromboprophylaxis, the incidence of venographically proven VTE ranges from 45 to 57% after total hip replacement (THR) surgery, 36 to 60% after hip fracture surgery (HFS), and 40 to 84% after total knee replacement (TKR) surgery.1 Multiple studies have established the superior efficacy of low-molecular-weight heparin (LMWH) over unfractionated heparin for VTE prophylaxis in orthopedic surgery patients, with relative risk reductions ranging from 44 to 70%, depending on the surgery type. However, because the baseline risk of VTE in these patients is high, despite optimal prophylaxis using LMWH, as many as one in six THR surgery patients, one in three TKR patients, and one in four HFS patients acquire postoperative "breakthrough" VTE.1 While rates of symptomatic postoperative breakthrough VTE are considerably lower, at 1 to 4%,2345 studies have demonstrated that 40 to 90% of such episodes manifest as proximal deep venous thrombosis (DVT),23 which is associated with a high risk of pulmonary embolism (PE).6
Identification of patient or surgical risk factors associated with the development of breakthrough VTE in orthopedic surgery patients could lead to better targeting of specific thromboprophylaxis modalities to these patients. For example, it is not clear whether traditional VTE risk factors such as previous thrombosis, malignancy, estrogen use, congestive heart failure (CHF), or paralysis increase the risk of breakthrough VTE. In the present study, we performed an analysis of risk factors for symptomatic breakthrough VTE in patients who underwent THR, TKR, or HFS over a 9-month period in a large tertiary care hospital.
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Materials and Methods
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Charts from all patients who underwent THR, TKR, or HFS (pinning or hemiarthroplasty) at our institution between August 1, 1999, and April 30, 2000, were retrieved and systematically reviewed using a standardized case report form. Patients who did not receive LMWH at the standard VTE prophylaxis dose as recommended by the thromboprophylaxis regimen for orthopedic surgery patients at our institution (see below) were excluded. Data were collected on baseline patient characteristics, type and side of surgery, operative factors (elective vs urgent, time to surgery, length of surgery, type and duration of anesthesia, use of cemented prosthesis), VTE risk factors (previous thrombosis, malignancy, active medical conditions, use of estrogenic compounds), and postoperative complications such as infection, CHF, myocardial infarction (MI), and bleeding. Bleeding was defined as overt if it was clinically evident and there was a clear source of bleeding. We also recorded type, duration, and dose of LMWH used for prophylaxis. Finally, we documented the results of any tests performed for suspected symptomatic VTE (eg, compression venous ultrasound, ventilation-perfusion scan) in the study population. Charts were reviewed for a minimum of 1 year following the index admission to capture any subsequent emergency department visits or hospital admissions for VTE. This study was approved by the Research Ethics Committee of our institution.
Thromboprophylaxis Regimen
Since 1995, our institution has used enoxaparin, 30 mg subcutaneous bid, begun within 12 h postoperatively and continued for at least 7 days for thromboprophylaxis in all THR, TKR, and HFS patients who have no contraindications to its use. In October 1999, the Pharmacy and Therapeutics Committee decided, for administrative reasons, to substitute enoxaparin with dalteparin, 5,000 U subcutaneous qd. Four months later, because of a perception on the part of nursing staff that there were more instances of postoperative VTE than usual during the preceding few months, the thromboprophylactic regimen was changed back to enoxaparin. This study was subsequently undertaken in part to try to objectively substantiate or refute this perception. In order to capture the change in thromboprophylaxis drug regimen in our study, the time window we examined included the 4 months of dalteparin use, as well as the 3 months prior to and the 2 months following the period of dalteparin use, when enoxaparin was used.
Statistical Analysis
The aim of the analysis was to calculate the incidence of symptomatic breakthrough VTE in our population and to identify patient, surgical, or thromboprophylaxis characteristics that were predictive of VTE. Comparisons of patients with and without VTE were made using 
2 test, Fisher Exact Test, or Student t test; p values < 0.05 were considered to indicate statistical significance. Logistic regression analysis was used to evaluate the association between breakthrough VTE and predictor variables of interest. Predictors achieving statistical significance were reported as an odds ratio (OR) with an associated 95% confidence interval (CI).
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Results
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Between August 1, 1999, and April 30, 2000, 385 patients were admitted to the Orthopedic Service for major orthopedic surgery. Of these, 75 patients were excluded because review of their charts showed that they did not receive the standard dose of LMWH for thromboprophylaxis, they did not receive any thromboprophylaxis, or they did not undergo surgery.
Baseline, Surgical, and Thromboprophylaxis Characteristics
Baseline characteristics of the 310 study patients are shown in Table 1
. The mean age of the patients was 72 years, two thirds of whom were female. Surgical characteristics of the study population are shown in Table 2
. HFS patients had a longer average length of stay and shorter operating times compared with THR and TKR patients. All THR and TKR surgeries were elective while HFS were considered urgent. The majority of the patients underwent spinal anesthesia. All patients received thromboprophylaxis with LMWH. Details of the thromboprophylaxis regimens received are shown in Table 3
. Half the study group received enoxaparin and half received dalteparin; the average duration of prophylaxis in both groups was 7 days. The initial dose was administered postoperatively in 305 patients (median of 8.5 h postoperatively in both groups), and preoperatively in 5 patients (enoxaparin n = 3; dalteparin, n = 2; mean, 27 h preoperatively). There were nine overt episodes of bleeding; none were intracranial. There was no difference in the frequency of overt bleeding in patients who received enoxaparin compared with those who received dalteparin (four bleeds and five bleeds, respectively).
Incidence of Suspected and Confirmed VTE
There were 83 cases of suspected VTE (74 suspected DVT, 6 suspected PE, and 3 suspected both). Doppler ultrasound was the diagnostic test performed in 82 patients, ventilation-perfusion scan in 2 patients, and spiral CT scan in 1 patient (3 patients had more than one test). The proportion of patients with suspected VTE was similar in all three study time periods (25%, 29.9%, and 21.2%, respectively; p = 0.42). There were 44 confirmed symptomatic VTE events (14% of study population); of these, 7 were proximal DVT and 37 were distal DVT. There were no episodes of pulmonary embolism (Fig 1
). Of the distal DVTs, 20 were located in the calf muscle (soleal) veins. DVT was diagnosed a median of 6 days (interquartile range, 4 to 7 days) postoperatively for TKR patients, 8 days (interquartile range, 5 to 15 days) postoperatively for THR patients, and 7 days (interquartile range, 5 to 15 days) postoperatively for HFS patients.
Predictors of VTE
On univariate analysis, TKR surgery (p = 0.0005), elective surgery (p = 0.041), and use of cemented prosthesis (p = 0.002) were significantly associated with breakthrough VTE (Tables 4, 5
). In addition, there was a trend suggesting a higher frequency of VTE in patients who received prophylaxis with dalteparin compared with enoxaparin (18% vs 10%, p = 0.085). Logistic regression analysis revealed that TKR surgery (OR, 4.8; 95% CI, 2.3 to 10.1; p < 0.001) and type of LMWH (OR for enoxaparin, 0.4; 95% CI, 0.2 to 0.8; p = 0.009) were the only variables that independently predicted VTE. Patient characteristics (including age, sex, previous thrombosis, malignancy, CHF, or recent MI, use of hormone replacement therapy, being bed bound, or postoperative complications) were not associated with VTE in either univariate or multivariate analyses. When the data were reanalyzed excluding patients with soleal vein DVT, results of the multivariate analysis were similar: TKR OR, 4.7; 95% CI, 1.8 to 12.3 (p = 0.0014); and enoxaparin OR, 0.2; 95% CI, 0.1 to 0.5 (p = 0.0017).
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Discussion
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We studied the incidence and predictors of symptomatic breakthrough VTE in patients undergoing orthopedic surgery at a large tertiary care hospital. We found that the rate of symptomatic VTE was high, and that knee surgery and type of LWMH used for prophylaxis independently predicted symptomatic breakthrough VTE. Patient characteristics, operative factors, and traditional VTE risk factors were not independently associated with VTE in our study patients.
Our study consisted of a typical patient population undergoing orthopedic surgery in a tertiary care setting. The frequency of symptomatic breakthrough VTE was 14% in our study population. Several previous studies2345 of orthopedic surgery patients found that the rates of symptomatic VTE after similar durations of LMWH prophylaxis were 1 to 4%. The reason for the higher rate in our study is uncertain but may include a higher risk population with a greater proportion of geriatric patients than that of other studies, or a lower threshold for testing at our center. As clinical examination for DVT in the context of orthopedic surgery has poor predictive value,7 patients with symptoms caused by the surgery itself (eg, pain, lower leg swelling) may be sent for venous ultrasound and have DVT diagnosed, thereby misclassifying the DVT as being symptomatic.
In studies23 of symptomatic DVT after orthopedic surgery, the proportion of DVTs that were proximal ranged from 50 to 90% in THR patients and from 40 to 50% in TKR patients; however, only 16% of the DVTs diagnosed in our patients were proximal, and there were no pulmonary emboli. Most postoperative DVTs begin in the deep veins of the calf. Isolated distal DVT has a negligible rate of PE; however, without treatment, one in six asymptomatic distal DVTs, and up to one in three symptomatic distal DVTs will extend to involve the proximal veins.6 Symptomatic proximal DVT carries a 40 to 50% rate of PE if left untreated.6 In addition to the risk of proximal propagation and PE, DVT is associated with postthrombotic syndrome (PTS) in 20 to 50% of cases, irrespective of initial site of thrombosis.9 Treatment with heparin followed by vitamin K antagonists prevents extension of thrombosis, reduces recurrent thrombosis, and permits endogenous lysis of the clot. Prevention of DVT is of utmost importance for PTS prevention, as treatment modalities for established PTS are of limited efficacy.8 A higher degree of clinical suspicion prior to ordering Doppler ultrasound likely increases the probability of detecting proximal DVT at the expense of missing some distal DVTs, which have a low incidence of proximal propagation. The median time to diagnosis in our patients was 6 days in TKR patients, 8 days in THR patients, and 7 days in HFS patients, consistent with previous reports9 that the time course of development of postoperative VTE is earlier in TKR patients. In one study,10 median time to diagnosis was 17 days after THR and 7 days after TKR.
Knee surgery has an extremely high risk of breakthrough VTE despite optimal thromboprophylaxis with LMWH. Multiple studies that used postoperative venographic screening have demonstrated a frequency as high as 30% in TKR patients, significantly higher than after THR or HFS.1 The rate of symptomatic DVT in our TKR patients was 26%, more than twofold higher than in our THR and HFS patients. Evidence suggests that venous thrombosis is initiated at the time of surgery, partly due to tourniquet use, as well as trauma to the endothelium of the deep veins of the leg during manipulation and placement of hardware.11 In two meta-analyses1213 of thromboembolism prophylaxis after TKR, LMWH prophylaxis was shown to be more effective than warfarin or aspirin in prevention of VTE and to have similar effectiveness to intermittent pneumatic compression. However, no studies comparing the efficacy of combined LMWH and intermittent pneumatic compression with either modality alone have been performed. Some authors111415 advocate multimodality regimens for knee surgery patients using combinations that target the intraoperative as well as postoperative period that may include intraoperative heparin, hypotensive epidural anesthesia, external pneumatic compression boots, and aspirin. Though results indicate a low incidence of asymptomatic VTE with these protocols, it is unclear which combination of these regimens is most effective, and whether the occurrence of symptomatic VTE is reduced as well. Our results support the need for multimodality regimens to further decrease the rate of breakthrough VTE in TKR patients.
Traditional VTE risk factors including previous VTE, age, gender, thrombophilia, obesity, malignancy, heart failure or recent MI, and stasis are known to increase the risk of VTE twofold to ninefold.16 However, given the extremely high risk of VTE in orthopedic patients, the relative contribution of some of these risk factors may be minimal. Studies9 have shown that prior thromboembolism and presence of malignancy, especially adenocarcinoma, are associated with at least a twofold increased risk of VTE in orthopedic surgery patients. Obesity with a body mass index (BMI) > 25 also increases the risk of postoperative symptomatic VTE, which is likely related to underdosing of LMWH and ineffectiveness of mechanical prophylaxis such as pneumatic compression.9 Thrombophilic disorders may increase the risk of breakthrough VTE; however, the extent of risk is unclear, and the need to screen orthopedic surgery patients for these disorders has yet to be determined.9 Our study did not find independent associations between traditional VTE risk factors and breakthrough VTE. However, the overall low prevalence of these risk factors in our population may have limited the power of the study to detect associations.
Our finding that patients who received prophylaxis with enoxaparin rather than dalteparin had a lower incidence of breakthrough VTE is noteworthy. LMWHs are distinct drugs, with variability in average molecular weights, specific composition, and anti-Xa activity. The anti-Xa activity is one of several antithrombotic properties of these agents and does not correlate directly with the antithrombotic effects of the different LMWHs.17 In a pharmacokinetic study18 of dalteparin and enoxaparin, enoxaparin had a higher anti Xa retention time and higher bioavailability. Twice-daily dosing of enoxaparin compared with the once-daily dose of dalteparin may result in a more uniform anticoagulant profile and thus may explain the difference between drugs that was found in our study. There are only two randomized, prospective trials directly comparing different LMWH compounds in orthopedic surgery. Both were composed of THR patients, and compared enoxaparin with reviparin in the first study,19 and enoxaparin with tinzaparin in the second study.20 Screening venography was used for DVT detection. In both trials, efficacy of the two heparins was equivalent with respect to both total number of DVT, proximal DVT, and bleeding complications. In the cardiac literature, differences in efficacy among LMWHs have been recognized. Studies21 with enoxaparin in acute coronary syndrome demonstrated its greater efficacy compared with unfractionated heparin in preventing the combined end point of death and MI, while a large study22 using dalteparin failed to show this benefit. Although the reason for this is unclear, these results point to the heterogeneity among the LMWHs not only in their pharmacokinetics, but in their clinical effectiveness. Our retrospective analysis found enoxaparin to be more effective than dalteparin in preventing symptomatic VTE. Whether this difference occurred by chance, is related to true differences in drug effectiveness in this clinical setting, or relates to advantages of using a twice-daily rather than once-daily regimen is uncertain. More definitive study of this issue by randomized controlled trials seems warranted.
We recognize that our study has several limitations. The retrospective design introduces the possibility of missing or incorrect data on VTE risk factors in the medical record. For example, data on previous thrombophilia workup were not readily available in the hospital chart. This may have limited the power of the study to detect associations between breakthrough VTE and traditional VTE risk factors. As well, because BMI was unavailable, we cannot exclude the presence of obese patients with BMI > 30, for whom the usual prophylactic dose of LMWH may have been subtherapeutic. To reduce this possibility, the entire chart was reviewed using standardized case report forms, including all previous hospital admissions and future admissions up to 1 year after the index admission. As well, the average duration of prophylaxis in our patient population was 7 days, which was the standard of care at the time the study was conducted. Since then, prolonged prophylaxis (up to 35 days) has been demonstrated to significantly decrease the frequency of venographically proven VTE in orthopedic surgery23 and likely decreases symptomatic VTE as well.24 We cannot speculate on whether the differences between LMWH compounds that we found would have been apparent with longer durations of prophylaxis. However, the impact of prolonged thromboprophylaxis after TKR surgery may be less significant due to the earlier onset of VTE postoperatively in such patients. Finally, we recognize that because symptoms prompted VTE testing, suspicion bias can result in an apparent higher rate of disease in one group vs another. However, we feel this is unlikely because there was no difference in the proportion of patients with suspected VTE (ie, who then underwent diagnostic testing) in the three time periods, there were similar rates of DVT in the enoxaparin group both before and after the switch to dalteparin, and concerns prompting the switch back to enoxaparin occurred very close to the end of the dalteparin period.
In conclusion, symptomatic breakthrough VTE developed in 14% of patients undergoing major orthopedic surgery despite standard thromboprophylaxis with LMWH. TKR patients are at higher risk for VTE and may benefit from more aggressive postoperative physiotherapy and ambulation as well as adjunctive prophylactic measures such as intermittent pneumatic compression. Our finding that use of enoxaparin was associated with a lower rate of VTE than use of dalteparin should be considered hypothesis generating, but suggests that further direct comparison of the relative efficacy of different LMWH compounds in the prevention of VTE in orthopedic surgery patients should be undertaken.
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Acknowledgements
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We thank Ms. Rosalie Johnson, RN, for administrative assistance.
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Footnotes
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Abbreviations: BMI = body mass index; CHF = congestive heart failure; CI = confidence interval; DVT = deep venous thrombosis; HFS = hip fracture surgery; LMWH = low-molecular-weight heparin; MI = myocardial infarction; OR = odds ratio; PE = pulmonary embolism; PTS = postthrombotic syndrome; THR = total hip replacement; TKR = total knee replacement; VTE = venous thromboembolism
Drs. Kahn and Shrier are recipients of Clinical Investigator Awards from the Fonds de la Recherche en Santé du Québec. This study was funded in part by an unrestricted grant-in-aid from Aventis to Dr. S. Kahn. The study sponsor had no role in the design and conduct of the study, the collection, management, analysis, interpretation and reporting of study data, the writing of the manuscript or the decision to submit the manuscript for publication.
This work was presented in part, as an abstract, at the Canadian Society of Internal Medicine Annual Meeting, Quebec City, Canada, June 2004.
Received for publication December 4, 2004.
Accepted for publication May 11, 2005.
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References
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Abstract
Introduction
