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Timing of Prophylactic Anticoagulation and Its Effect on Thromboembolic Events After Surgery for Metastatic Tumors of the Spine

De la Garza Ramos, Rafael, MD∗,†; Longo, Michael, BA; Gelfand, Yaroslav, MD∗,†; Echt, Murray, MD∗,†; Kinon, Merritt D., MD∗,†; Yassari, Reza, MD∗,†

doi: 10.1097/BRS.0000000000002944
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Study Design. Retrospective cohort study.

Objective. To investigate the effect of timing of initiation of prophylactic anticoagulation (AC) on the incidence of venous thromboembolism (VTE) after surgery for metastatic tumors of the spine.

Summary of Background Data. VTE is a known complication in patients undergoing surgery for metastatic spine disease. However, there is limited data on the use of prophylactic AC in this population and its impact on the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the risk of epidural hematoma.

Methods. A retrospective review of our institutional neurosurgical spine database for the years 2012 through 2018 was performed. Patients who underwent surgery for metastatic tumors were identified. The development of VTE within 30 days was examined, as well as the occurrence of epidural hematoma. The incidence of VTE was compared between patients receiving “early” (within postoperative days 1–3) and “delayed” prophylactic AC (on or after postoperative day 4).

Results. Sixty-five consecutive patients were identified (mean age 57, 62% male). The overall rate of VTE was 16.9%—all of whom had DVTs with a 3.1% rate of nonfatal PE (two patients also developed PE). From the overall cohort, 36 of 65 (56%) received prophylactic AC in addition to mechanical prophylaxis—22 in the early group (61.1%) and 14 in the delayed group (38.9%). The risk of VTE was 9.1% in the early group and 35.7% in the delayed group (26.6% absolute risk reduction; P = 0.049); there was one case of epidural hematoma (1.5%). On multivariate analysis, delayed prophylactic AC was found to significantly increase the odds of VTE development (OR 6.43; 95% CI, 1.01–41.2; P = 0.049).

Conclusion. The findings of this study suggest that administration of prophylactic AC between days 1 and 3 after surgery for metastatic tumors of the spine may significantly reduce the risk of postoperative thromboembolic events.

Level of Evidence: 4

In this retrospective cohort study, the incidence of venous thromboembolism in patients who underwent surgery for metastatic tumors of the spine was investigated. Administration of prophylactic anticoagulation between days 1 and 3 after surgery significantly reduced the risk of postoperative thromboembolic events.

Spine Research Group, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY

Department of Neurological Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.

Address correspondence and reprint requests to Rafael De la Garza Ramos, MD, 3316 Rochambeau Avenue, 3rd floor, Bronx, NY 10467; E-mail: rafdelag@gmail.com

Received 7 August, 2018

Revised 18 September, 2018

Accepted 26 October, 2018

The manuscript submitted does not contain information about medical device(s)/drug(s).

No funds were received in support of this work.

Relevant financial activities outside the submitted work: consultancy.

The spine is the most common site for skeletal metastases. Cancer is a known hypercoagulable state, putting patients at risk of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE).1 Although the former may cause problems such as leg/calf pain, the most dreaded complication is progression to PE, which can be a fatal condition.

Surgical management of metastatic tumors to the spine is usually reserved for patients with acute neurological deficits, gross instability causing deficits or intractable pain, and for patients with a relatively good short-term prognosis.2 The risk of VTE after spine surgery varies throughout the literature, with studies showing rates between 1% and 22% in tumor patients.3–9 Although a majority of patients undergo mechanical prophylaxis to prevent DVTs, there is a lack of guidelines on the use and timing of prophylactic anticoagulation (AC) such as subcutaneous heparin or enoxaparin. Additionally, there is a potential risk of causing epidural bleeding and neural element compression, especially with more extensive procedures and high blood loss, which could further aggravate an already injured spinal cord.

Although the National Institute for Health and Care Excellent (NICE) advice spine surgeons to utilize clinical judgement when using prophylactic AC, no guidelines exist on the timing of initiation.10 Furthermore, there exists significant variability on both the use and timing of prophylactic AC, with very limited data on its use after surgery for metastatic spinal disease.11 The purpose of this study is to examine the impact of timing of initiation of prophylactic AC on the incidence of DVT and PE after surgery for metastatic tumors of the spine.

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MATERIALS AND METHODS

Study Design and Data Source

This study received institutional review board approval (2016-6896). A retrospective review of our institutional neurosurgical spine operative database between 2012 and March 2018 was performed to identify adult patients who underwent surgery for metastatic spine disease. Patients without follow-up at 30 days were excluded. Indications for surgery included patients with metastatic epidural spinal cord compression (MESCC) causing neurological deficits and/or spinal instability. The decision to undergo operative versus nonoperative management was a consensus between patients/families and our interdisciplinary tumor board consisting of neurosurgeons, neuro-oncologists, and radiation oncologists, unless patients presented acutely with neurological deficits requiring emergency decompression.

All patients at our institution receive mechanical DVT prophylaxis in the form of sequential compression devices and undergo screening for DVT within the first postoperative week and weekly thereafter, or earlier if indicated on a case-by-case basis (calf pain, suspicion for PE, fever workup, etc.).

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Collected Data

The following patient data were collected from electronic medical charts and our operative database: patient age, sex, primary tumor location, body mass index (BMI), medical comorbidities (diabetes, hypertension, chronic lung disease, and coronary artery disease), smoking history, history of previous VTE, history of aspirin or anticoagulant use, Karnofksy status (<70 vs. > = 70), modified Bauer score, Spinal Instability Neoplastic Score (SINS), presence of MESCC, ambulatory status at presentation, surgical technique (laminectomy, fusion, corpectomy, etc.), and overall survival.

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Outcome Variables

Collected outcome data included use of prophylactic AC, timing of initiation, and development of VTE (DVT or PE) within 30 days after surgery; VTE occurring preoperatively, intraoperatively, or after 30 days were not categorized as developing VTE. Prophylactic agents included use of subcutaneous heparin or low-molecular weight heparin (enoxaparin or dalteparin). Patients who developed superficial vein thrombosis were not categorized as having developed VTE. Patients who received subcutaneous heparin or enoxaparin the same day they developed VTE were not categorized as having received prophylactic AC. The decision to start and when to start prophylactic AC was primarily dependent on the attending neurosurgeon and based on the perceived risk of developing VTE versus the risk of developing a hematoma given the invasiveness of surgery. Lastly, diagnoses of clinically-relevant epidural hematomas (evidenced by worsening neurological function and confirmed by magnetic resonance imaging or computed tomography) requiring surgical decompression were also analyzed. While all of our patients who receive instrumentation undergo postoperative CT scans within the first 72 hours, patients who only undergo decompression do not undergo routine imaging unless clinically indicated.

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Statistical Analysis

All analyses were performed in Stata SE 12. Two groups were established for analysis: patients receiving prophylactic AC on postoperative days 1 to 3 and patients receiving it from day 4 onward. Descriptive statistics were performed with parameters expressed as percentages or means with standard deviations (SD). Means were compared via analyses of variance and frequencies via chi-squared tests. Factors with a P value <0.100 on univariate analysis, along with age, sex, presence of MESCC, and ambulatory status, were included in a multivariate analysis with a backward stepwise selection process to determine the independent effect of timing of prophylactic AC on VTE development. Statistical significance was defined as a probability value < 0.05.

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RESULTS

A total of 65 consecutive patients operated on between 2012 and 2018 were identified from our operative database and included in this study. The average age for all patients was 57 years and 62% were male. The most prevalent primary tumor was lymphoma in 26.2% of cases, followed by prostate cancer in 15.4% and breast in 13.9% (Table 1). Average BMI for all patients was 27 kg/m2 (SD 5.9) and the two most common comorbidities were hypertension (47.7%) and smoking (43.1%) (Table 2). There were 6/65 patients (9.2%) with history of previous VTE who were on home anticoagulants. One-third of patients (33.9%) had a Karnofsky functional status less than 70. Average modified Bauer and SINS scores were 2.2 and 10.9, respectively. Twenty percent of patients were nonambulatory at presentation, in 78.5% a posterior decompression was performed, in 21.5% a corpectomy was performed, and 89.2% of patients underwent pedicle screw stabilization. Mean survival was 17 months.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Timing of Prophylactic AC

There were 36/65 patients (56%) who received prophylactic AC in addition to mechanical prophylaxis. Thirty-one patients received subcutaneous heparin, three patients received dalteparin, and two patients received enoxaparin as first agent. The mean day to start was postoperative day 3. There were 22 patients who received prophylactic AC from days 1 to 3 (61.1%; early group) and 14 who received in from day 4 onward (38.9%; delayed group).

General and operative demographics between the early and delayed groups are compared in Table 3. Average age (P = 0.202), sex (P = 0.171), and BMI (P = 0.568) were not found to be significantly different between groups. In terms of comorbidities, no significant differences were found between groups at a threshold P level of 0.05; however, 50% of patients in the delayed group were found to be smokers compared with 22.7% in the early group (P = 0.091) and this parameter was included in the multivariate model. Similarly, the modified Bauer score (P = 0.081) and use of laminectomy (P = 0.049) were also included in the regression model.

TABLE 3

TABLE 3

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Incidence of Venous Thromboembolism

The overall incidence of VTE was 11/65 (16.9%). All of them developed DVTs, with two patients subsequently developing nonfatal PE (3.1%). The rate of VTE was 9.1% in the early group (days 1–3) and 35.7% in the delayed group (26.6% absolute risk reduction; P = 0.049) (Figure 1). There was one case of epidural hematoma requiring surgical decompression (1.5% from the overall cohort; 2.8% for patients who received prophylactic AC vs. 0.0% for patients who did not, P = 0.366). This was a 60-year-old man with prostate cancer and history of aspirin use (stopped 1 wk before surgery) who underwent a T4-6 laminectomy, T5 transpedicular corpectomy, and T1-T8 transpedicular fixation. On postoperative day number two he developed weakness in both legs and CT of the thoracic spine showed focal compression at T4/5 from an epidural collection, for which patient underwent emergent evacuation of an epidural hematoma. This patient had received prophylactic AC on day two. Fortunately, he returned to his neurological baseline without further deficits.

Figure 1

Figure 1

A multivariate analysis controlling for patient age, sex, presence of MESCC, ambulatory status, smoking history, modified Bauer score, and use of laminectomy was performed to assess the independent effect of timing of prophylactic AC on development of VTE. This analysis showed that the delayed group did have a significantly higher risk of VTE compared with the early group (OR 6.43; 95% CI, 1.01–41.2; P = 0.049).

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DISCUSSION

VTE is a known complication in cancer patients and spine surgery patients. Patients with metastatic tumors to the spine who undergo surgery are at an increased risk of VTE compared with other pathologies such as spondylosis or deformity,8 owing to both the cancer itself and also to known associated conditions such as nonambulatory status, poor preoperative functional status, and surgical intervention. Although other surgical subspecialties have clear guidelines on the use of prophylactic AC postsurgically,12 no definitive guidelines exist for spine surgery patients, with further limited data on patients with spinal tumors.

In this study, we examined the incidence of VTE for patients who received early versus delayed prophylactic AC, finding a significantly lower incidence of VTE for patients who received anticoagulation within the first 3 postoperative days. There was an overall DVT/PE incidence of 16.9%, in addition to a 1.5% incidence of epidural hematoma. More importantly, the risk of VTE was 9.1% for patients receiving prophylactic AC within the first 3 days compared with 35.7% in patients receiving it after day 3, consistent with a 26.6% absolute risk reduction.

Commensurate with our findings, Yoshioka et al8 reported a 22% incidence of VTE in patients undergoing surgery for spinal tumors. In their study, the authors prospectively followed 340 patients who underwent spinal surgery and screened for DVT/PE during postoperative days 7 to 10. They found a 22% risk of VTE in patients undergoing surgery for tumors, compared with 15.2% for patients with spinal stenosis, 13.3% for thoracolumbar spondylosis, and 4.5% for patients with cervical spondylosis.8 Although our rate was similar to Yoshioka et al's (16.9% vs. 22%), other studies have found lower rates for patients with metastatic spine disease.13 While the exact reason for this finding is unclear, differences in rates may occur due to variability in screening protocols, detection methods, as well as studied populations. In our case, for example, our population has a much higher smoking prevalence than the national one (47.7% vs. 15%), which could also account for differences in VTE rates.14

Use and timing of prophylactic AC after spinal surgery is variable. Although VTE is a recognized perioperative complication, there are lack of guidelines and established protocols for patients who undergo surgery for metastatic spine disease. Furthermore, there exists concern for the development of epidural bleeding and further/new spinal cord compression and deficits. Kim et al15 performed a retrospective analysis at a level 1 trauma center and examined 206 patients who underwent surgery for spine fractures. They found that among patients receiving “early” prophylactic AC (within 48 hours) the rate of VTE was lower compared with patients who received it in a delayed fashion (though it did not reach statistical significance, probably due to the limitation in the power of the analysis). In addition, there was no increased risk of bleeding or neurological complications in their study.15 In a more recent investigation of 6869 patients using a single-center administrative database, the authors found that administration of prophylactic AC within the first 3 postoperative days did not increase the risk of epidural hematoma.16

However, none of the two previous studies addressed anticoagulation in patients with metastatic disease and it is thus difficult to generalize the results. Our findings suggest that patients who receive “early” prophylactic AC may in fact benefit from a reduced risk of VTE without a significant increase in the incidence of epidural hematoma. Although milder forms of epidural bleeding may have occurred, only one of our patients deteriorated neurologically to the point of necessitating emergency imaging and evacuation of an epidural hematoma. In their study of 6869 patients, Dhillon et al16 found a rate of epidural hematoma of 0.2%, with an average onset of 10.8 days—furthermore, only 25% of patients experienced neurological deficits. These findings suggest that this complication is indeed very rare and will only result in a clinically significant deficit in a subset of patients. Reported risk factors include high alcohol consumption, multilevel procedures, history of previous spinal surgery, history of coagulopathy or anticoagulant use, highly vascular lesions, and others.17–19

Although the most feared complication of DVT development is progression to PE, only two cases of PE were found in the present study (3.1%) and both cases were nonfatal. Overall, the findings of this study support the administration of early prophylactic AC in addition to mechanical prophylaxis as a potential method to decrease the risk of VTE after surgery for metastatic tumors of the spine, with a small and nonstatistically significant risk of epidural bleeding requiring surgical intervention.

These findings, however, should be corroborated by further investigations and ideally in a prospective and randomized trial. Although most patients who received prophylactic AC did so in the first 3 postoperative days (61.1%), the decision to start and when to start prophylactic AC was mostly surgeon-dependent and did not follow a specific protocol. Thus, this imposes an opportunity for further research and validation of the potential benefits of early administration of pharmacologic agents for VTE prevention.

While there was a significant difference in VTE rates based on timing of anticoagulation, other comparisons may not have been statistically significant given the sample size from a single institution compared with much higher numbers from national databases or multicenter studies. For example, there was a higher rate of patients with previous history of VTE and home anticoagulation in the early group, which may have led to a higher perceived risk of recurrent DVT/PE and thus an earlier initiation of prophylactic AC. Despite these limitations, the relative safety and potential benefit of early prophylactic AC in spine surgery has also been shown in previous studies,15,16 further supporting the findings presented herein.

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CONCLUSION

VTE is a known complication in patients undergoing surgery for metastatic tumors of the spine. In this study, administration of prophylactic AC in addition to mechanical prophylaxis between days 1 and 3 after surgical intervention significantly reduced the risk of DVT and PE occurring within 30 days, with a 26.6% absolute risk reduction. There was one case of epidural hematoma (1.5%). Although further research is needed ideally in a prospective randomized trial, these findings suggest that early prophylactic AC is a relatively safe practice and can potentially decrease the risk of thromboembolic events.

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References

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Keywords:

deep vein thrombosis; metastatic tumor; prophylactic anticoagulation; pulmonary embolism; spinal tumor

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