The occurrence of a PE is a rare phenomenon even in patients who have cancer, with historical rates in the early postoperative period following mechanical prophylaxis alone ranging from 0.4% to 3%7-11. Historically, DVT rates in patients who have had resection of a musculoskeletal tumor without chemical prophylaxis have tended to be much higher, with a reported prevalence of 40% to 80% for calf vein thrombosis and 10% to 20% for proximal vein thrombosis2,12. The present study demonstrated that patients who underwent prophylactic nailing because of an impending pathological femoral fracture tended to be younger and healthier than those who were managed with nailing after a fracture has occurred. Patients who underwent IMN after a pathological fracture also had more postoperative complications. Surprisingly, despite the aforementioned lower rates of serious medical comorbidities and postoperative complications, the patients in the prophylactic fixation group had significantly higher rates of PE and DVT.
The present study had a number of limitations, some of which are inherent to retrospective database analyses. Retrospective database analyses provide a very limited picture of only in-hospital events that only permits inference of the association between exposure and disease13. The present study demonstrated a significant difference between the 2 groups in terms of DVT and PE rates but cannot explain why the difference exists. Also, these analyses are subject to coding bias13 because certain fragility fractures may be miscoded by the treating surgeon as pathological fractures, with osteoporosis being the underlying pathological process. To address this potential bias, a validation study was conducted at our institution to cross-reference ICD-9 codes in the NIS with medical records; that study demonstrated that the accuracy of classification and diagnosis of metastatic disease to be acceptable (85% in Group A and 83% in Group B). Previous studies using the NIS database have also demonstrated acceptable accuracy and quality control14,15. If the pathological fracture group were “contaminated” with fragility fractures in osteoporotic patients, one would expect a lower incidence of comorbidities compared with the prophylactically-treated patients because osteoporotic patients tend to be healthier, on the average, than those with metastatic disease.
In addition, several important clinical variables that impact the rates of VTE were unreported in the database, including histological diagnosis, the size of lesion and/or burden of disease, adjuvant chemotherapy or radiotherapy, surgical details (e.g., whether polymethylmethacrylate was utilized or whether reaming was performed prior to nail insertion)16,17, and anticoagulation status. Certain types of malignant lesions, such as lung cancers, are associated with a higher risk of venous thrombosis or embolism8,18. A large tumor burden is associated with higher levels of procoagulant factors12,19-21 and a higher likelihood of thrombotic events22. Chemotherapeutic agents and hormonal treatments used for certain types of metastatic disease contribute to the risk of thrombosis23-26. Similarly, radiotherapy is also associated with DVT when it is used to treat lymphoma and certain gynecological malignant lesions27,28. Therefore, it is possible that 1 of the treatment groups might have had a larger proportion of patients with these confounders.
Another limitation was the lack of specific anticoagulation data during hospitalization and after discharge. Shallop et al.18 demonstrated that patients with metastatic bone lesions had a high rate of VTE after intramedullary nail fixation (7.1%; 24 events in 336 impending or pathological fractures) despite current anticoagulation protocols. Low-molecular-weight heparin was the most commonly used chemoprophylaxis in their overall cohort and in the subset of 19 patients who had a DVT or PE during the perioperative period. Of those 19 patients, 18 had undergone prophylactic fixation because of an impending fracture while 1 had fixation of a pathological fracture, which corroborates our findings. A thorough multivariate analysis was performed in the present study to adjust for the large number of potential confounders. Our large sample size ensures that mean values will not be greatly influenced by coding bias, minimizing type-II error.
Because the database only included information on perioperative complications that occurred during the index admission, we were unable to determine late complication rates or post-discharge mortality and VTE rates. In the study by Shallop et al.18, the majority of VTE cases (74%; 14 of 19) that occurred after IMN fixation for the treatment of metastatic bone lesions occurred during the first 15 days after surgery. Therefore, the results of the present study cannot be generalized to the overall rate of VTE or the long-term risk of VTE after surgery. The NIS database further limits the ability to assess the associated postoperative complications and outcome measures diagnosed after hospital discharge. Therefore, the presented rates of DVT, PE, and death are likely underestimated and may potentially be even higher in both groups with a longer follow-up period. Nevertheless, these results are valuable for examining immediate postoperative rates of VTE and complications after IMN for the treatment of pathological lesions.
The weakness of the present study is the inability to provide definitive explanation for why the prophylactic fixation group had higher rates of DVT and PE. Overall, patients with metastatic femoral disease likely have compromised lung function before surgery as well as multiple medical comorbidities in addition to possible pulmonary parenchymal metastatic disease. Such patients also have hypervascular tumor foci in bone with a larger surface area of vascularity that can intravasate activated inflammatory mediators, fat emboli, and hypercoagulable cancer cells, placing them at higher risk for pulmonary complications. The adult reconstruction literature has demonstrated an association between fat and marrow embolism and VTE, with some authors theorizing that marrow fat intravasation with insertion of the femoral component during total hip arthroplasty leads to endothelial injury and the onset of a coagulation cascade29,30. In the case of metastatic bone lesions, reaming or instrumentation of an intact femur increases the intramedullary pressure and may result in intravasation of fat and thrombogenic material into the systemic circulation, leading to increased endothelial damage and hypercoagulability. This phenomenon has been observed in patients managed with prophylactic IMN for the treatment of impending fractures from metastatic lesions31,32 and in previous cadaveric studies33,34. Accordingly, Wilkens et al.35 suggested making a vent hole to decompress the femoral canal prior to nailing the femur. However, this technique has not been widely investigated clinically.
The higher observed rates of VTE in the prophylactic fixation group in the present study should not dissuade surgeons from prophylactic stabilization of an impending pathological fracture but rather should serve as an important reminder to remain vigilant about VTE prevention. Patients who present with impending fractures for prophylactic fixation tend to be younger and healthier, with a presumed lesser burden of disease, in comparison with patients with pathological fractures, but they remain at a considerable risk for having an acute VTE. The decision to treat a metastatic lesion with prophylactic nailing as opposed to nonoperatively is based on individual clinical judgment, which is outside the scope of the present study. Recent technological advances with computed tomography-based rigidity analysis (CTRA)36,37 may provide an improved method of predicting the risk of pathological fracture resulting from long-bone metastasis as compared with the Mirels scoring system38.
The present study, similar to the literature, demonstrated that prophylactic fixation was associated with a lower rate of acute postoperative comorbidities and a greater likelihood of being discharged to home even after adjusting for sex, age, and comorbidities (p < 0.001). Ward et al.5, in a study of 182 patients, demonstrated that IMN for prophylactic fixation of femoral metastases resulted in decreased morbidity and mortality at 1 and 2 years, with a decreased average blood loss, a shorter hospital stay, a greater likelihood of discharge to home as opposed to an extended-care facility, and a greater likelihood of retaining walking ability without assistive devices as compared with pathological fracture fixation. Multiple other studies also have demonstrated better overall survival at all postoperative time points in patients managed with prophylactic stabilization4,6,39. Janssen et al.40 compared the rates of revisions and complications for 3 types of fixation (IMN, endoprosthetic reconstruction, and open reduction and internal fixation) for metastatic disease or multiple myeloma of the proximal part of the femur. They found a rate of PE (2.3%) similar to that in the present study after IMN procedures, the majority of which were performed for prophylactic fixation. They further revealed no difference in revision and complication rates between the 3 surgical techniques but did not stratify the analysis into prophylactic and post-fracture groups.
Contrary to previous reports that have demonstrated longer hospital stays for patients with pathological femoral fractures4,5, the length of stay did not differ between the 2 groups in our series. Earlier mobilization after fracture fixation with IMN and increased availability of outpatient rehabilitation may explain the earlier discharge. These changes coincide with the economic transformation in healthcare associated with the aim of minimizing inpatient cost. For example, Ristevski et al.4, in a study of patients who were managed with femoral stabilization in Canada during the 1990s, reported a mean length of stay of 19.3 days for the prophylactic treatment group compared with 24.3 for the pathological fracture group. In the present study, which included incentivized hospitals in the U.S., the mean lengths of stay were 7.49 and 7.54 days for the prophylactic fixation and pathological fracture groups, respectively, representing an approximately threefold decrease compared with the values reported by Ristevski et al.4. Last, it is pertinent to note the similarity in racial and socioeconomic background between the 2 groups of patients, indicating that these factors did not likely influence the treatment received by the patient. This finding is in direct contrast to the disparity in care for other orthopaedic procedures in the published literature41,42.
In conclusion, patients who underwent prophylactic treatment of metastatic femoral disease with IMN tended to be younger and healthier than those who were managed with IMN after a pathological fracture. Similar to previous reports in the literature, our study demonstrated that patients with a pathological fracture had increased rate of acute postoperative complications and were less likely to be discharged to home. After adjustment for age, sex, and preexisting comorbidities, the rates of PE and DVT remained higher in the prophylactic nailing group than in the pathological fracture group. The present study is not intended to argue against the use of prophylactic fixation for indicated patients but rather to serve as a caution that patients with metastatic disease who undergo prophylactic nailing should be vigilantly managed to decrease the rate of postoperative symptomatic VTE. Prospective studies are warranted to evaluate and optimize DVT prophylaxis protocols for patients undergoing surgery for the treatment of metastatic bone disease.
Tables showing results of the multivariate analysis are available with the online version of this article as a data supplement at jbjs.org (http://links.lww.com/JBJS/A7).
Investigation performed at the Department of Orthopaedic Surgery, University of Chicago, Chicago, and the Department of Orthopaedic Surgery, Northwestern University, Chicago, Illinois
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