VTE is one of the most common major complications and reasons for readmission, and ICH the most common reason for reoperation among patients undergoing craniotomy for primary malignant brain tumors. This multicenter study provides novel and useful information regarding the timing of these events and identification of high-risk patients. The increased risk of VTE extends beyond the period of hospitalization, especially for PE, whereas ICH occurs predominantly within the first days after surgery. The VTE risk profile depends on the type of VTE (DVT vs. PE events) and the clinical setting (hospitalized vs. post-discharge patients).
The patient population in this study was technically classified as all those with primary malignant brain tumors based on ICD-9 codes. Gliomas represent close to 80% of primary malignant brain tumors [
38], however, there is no standard ICD-9 code specific for glioma. The Central Brain Tumor Registry of the United States (CBTRUS) argues that multiple combinations of ICD histology codes can be used to define gliomas, and their approach was modeled in this study [
38]. Therefore, these results are primarily applicable to glioma patients and should be put in the context of previous outcome research on glioma patients.
Previous work
Several multicenter studies have previously investigated the short-term incidence of and risk factors for VTE after brain tumor surgery [
3,
13,
39‐
45], of which four studies focused on glioma patients [
3,
13,
39,
41]. From these studies, the rate of VTE following craniotomy is cited as 3.3–7.5% for glioma patients [
3,
13,
39,
41] and 2.3–4.0% for brain tumors patients in general [
11,
40‐
42,
44], with a follow-up ranging from solely the initial hospital stay to 6 weeks after surgery. The 30-day VTE rate was as high as 9.3% when asymptomatic DVTs were included too [
3]. These results are comparable to the VTE rates found in the current study and suggest a higher rate of VTE in glioma patients postoperatively compared to other brain tumors.
Simanek et al. assessed the cumulative incidence of VTE over time after craniotomy for gliomas, demonstrating a major increase in the number of events in the first 3 months after surgery; however, no granular insight into the distribution of events within the first few weeks postoperatively was provided due to a low sample size. Neither did this study stratify for VTE type or the clinical setting of the patient [
4].
Risk factors identified for VTE after craniotomy for gliomas are older age, history of craniotomy, history of VTE, coagulopathy, seizures, increased stay on the intensive care unit, prolonged hospital stay, residual tumor tissue, and absence of thromboprophylactic therapy [
3,
4,
6,
12‐
15]. Missios et al. stratified for VTE type demonstrating different risk profiles for postoperative DVT and PE. Male gender, Hispanic ethnicity, and medium bed size were predictive for PE, whereas chronic heart failure was predictive for DVT [
3]. Other predictors of postoperative VTE identified in the broader group of brain tumor patients were higher BMI, hypertension, functional dependence, lower Karnofsky Performance Scale (KPS) score, motor deficits, ventilator dependence, steroid usage, preoperative sepsis, longer operative times, and higher World Health Organization (WHO) tumor grade [
11,
40,
42,
43,
46].
Prophylactic anticoagulation is a commonly used strategy to prevent VTE but should be carefully balanced against the risk of ICH. In previous studies, the rates of ICH following craniotomy for brain tumors is cited as 1.0–4.0% with a follow-up ranging between the initial hospital stay and long-term survival after surgery [
6,
13‐
15,
44,
46‐
48]. However, definitions for major ICH varied between volumetric measurement of the hematoma, presence of symptoms, decrease in hemoglobin, or need for surgical evacuation of hematoma [
14,
15,
21,
23,
24,
49].
Mantia et al. assessed the cumulative incidence of ICH over time after craniotomy for glioma. However, no time-to-event analysis was provided for the direct postoperative period due to a low sample size [
23]. Neither did this study stratify for the clinical setting of the patient. Risk factors associated with ICH were history of craniotomy, use of bevacizumab, and therapeutic anticoagulation for VTE [
13,
20‐
24]. The association between thromboprophylactic anticoagulation and ICH remains to be elucidated [
15].
To our knowledge, the current study is the first large multicenter assessment including a descriptive time-to-event analysis for both VTE and ICH within 30 days after craniotomy for primary malignant brain tumors. Additionally, it is the first study that uses the NSQIP database to identify predictors of ICH after brain tumor resection. By addressing thrombotic outcomes as well as hemorrhagic outcomes, this study provides a meaningful direction for future research on thromboprophylactic treatment strategies. Lastly, the large sample size allows a stratification of both the descriptive and inferential analysis, demonstrating differences in risk profile and incidence over time based on VTE type (DVT vs. PE) and clinical setting (hospitalized vs. post-discharge patients).
Limitations
Complication rates found in the current study can be conservative estimates if events were not reported back to the hospitals. VTEs were only coded as events if they were diagnosed and treated, thereby missing asymptomatic and undetected VTEs. The database additionally lacks several demographic variables identified in other studies as predictors. Tumor specific information (histology, size, location, residual tumor volume) and complication specific information (location and classification of DVT, PE, and ICH) was not available. However, both VTE and ICH were defined in the NSQIP database as complications requiring medical and surgical treatment, respectively, resulting in selection of the most clinically relevant events. Perhaps most importantly, no data is available regarding anticoagulation status and non-pharmaceutical prophylactic methods. Therefore, this study offers limited insight in the efficacy of different thromboprophylactic treatment strategies and their association with the occurrence of ICH. Selection bias can be introduced since institutions can selectively contribute patients to the NSQIP registry. There was a lower number of events due to separate analyses based on VTE type and clinical setting; however, our study was not underpowered for most outcome measures according to rule of 10 events per variable in the multivariable analysis [
50]. Lastly, VTE and ICH events after the 30-day time period established in NSQIP are not accounted for in this study, although studies have demonstrated that the risk of VTE events remains non-negligible beyond 30 days postoperatively with incidences up to 26% in the first 12 months postoperatively [
4‐
6]. Despite these limitations, this study provides useful insight into the rates, timing, and predictors of DVT, PE, and ICH after craniotomy for primary malignant brain tumors. Due to the multicenter nature of the NSQIP dataset, the results of this study may be more representative of typical management at all hospitals, including but not limited to tertiary care academic centers.
Implications
The significant prevalence of VTE and ICH following craniotomy for primary malignant brain tumors found in the current study indicates that there is still room for improvement when it comes to monitoring and preventing these events. Rolston et al. demonstrated that the prevalence of VTE following a neurosurgical procedure registered in NSQIP has remained consistent over the last years [
51]. This suggests that perioperative management still hasn’t improved effectively with regards to preventing VTE, despite the attention it receives in neurosurgical literature.
These results particularly encourage the need for continued awareness for VTE post-discharge, especially for PE, which has more lethal consequences. These PEs can also be considered more sudden since they were less often preceded by a known DVT. PEs preceded by a DVT, however, suggest inadequate treatment for the initial VTE event. It is possible that DVTs are less frequent post-discharge. It is our primary suspicion, however, that DVTs are underdetected after leaving the hospital because they are less frequently symptomatic and cannot be effectively screened for. It is also possible that patients develop symptomatic DVTs but are unaware of the signs and symptoms until they progress to PE, implicating a possible role for improved patient education in preventing morbidity caused by DVT and PE. In prospective randomized control trials investigating different VTE prophylaxis modalities, Goldhaber et al. screened all craniotomy patients prior to discharge and found 9.3% of patients to have VTE, most of which were asymptomatic in both studies [
45].
Most guidelines recommend that prophylactic use of low-molecular weight heparin or unfractionated heparin should be considered in all cancer patients undergoing major surgery [
16‐
19]. In patients undergoing operations for brain tumors, however, the benefits of anticoagulation should be carefully balanced against the risk of ICH [
52,
53]. Although most guidelines support the use of pharmacological prophylaxis in patients with brain tumors, proper timing of prophylaxis remains controversial and the use of anticoagulation often depends on the surgeon’s preference [
52‐
54]. Recommendations vary between administration throughout hospitalization [
19], up to 7–10 days after surgery [
16,
17,
55], until the patient is mobile [
52], or timing based on the individual risk profile [
56]. A lack of scientific evidence is primarily the cause of this variation in recommendations. Recent systematic reviews and meta-analyses of VTE prophylaxis in patients undergoing craniotomy for brain tumors have been performed [
42,
57‐
60]. These analyses have compared different VTE prophylaxis modalities, as well as their safety and cost effectiveness, but they do not thoroughly investigate the efficacy of prophylaxis over time to determine a recommended duration. Only one clinical trial studied the effect of continued prophylaxis up to 12 months after surgery [
15]. No significant association was found between prolonged prophylaxis and the rate of both VTE and ICH; however, the trial was stopped early because of expiration of study medication, and the control group received placebo instead of short-term prophylaxis. Many patients may not need or benefit from continuing thromboprophylactic therapy beyond discharge. Algattas et al. reviewed the safety and effectiveness of thromboprophylactic strategies and indicated that different regimens may have different efficacies depending on the patient’s VTE risk profile [
57]. This highlights the importance of using the appropriate risk profile for optimizing postoperative management.
Since the NSQIP data does not contain information on thromboprophylactic strategies, the current study provides limited insight into the efficacy or safety of prophylactic anticoagulation and insufficient evidence to change the current clinical practice of thromboprophylaxis in patients undergoing operations for primary malignant brain tumors. Therefore, we concur with the current guidelines that recommend pharmaceutic prophylaxis (low-molecular weight heparin or unfractionated heparin) in combination with mechanical prophylaxis (anti-embolism stockings or intermittent pneumatic compression devices) postoperatively until the end of hospitalization or until the patient is mobile. Absolute contra-indications for these include recent ICH or another active major bleeding [
16‐
19,
52,
53,
55,
56].
Suggestions for future research
Despite its limitations, this study provides useful insight into the prevalence, timing, and risk factors of postoperative VTE and ICH after craniotomy for primary malignant brain tumors. The results of the current study demonstrate that there is still room for improvement, especially with regard to the prevention of PE after hospitalization. The distinct critical time periods for both thrombotic and hemorrhagic events suggest a potentially safe and effective role for continuing prophylactic anticoagulation post-discharge in high-risk patients. Additionally, the typical patient at risk for developing a VTE during hospitalization is not the same as the typical patient at risk for developing a VTE post-discharge. This is crucial for tailoring post-discharge management to the risk profile of the individual patient and suggests an important direction for future research. Therefore, future research should study the effects of timing of thromboprophylactic therapy, screening for asymptomatic events, and the effects of patient education on the occurrence of VTE and/or ICH. Additionally, future studies should construct prediction models for DVT, PE, and ICH and examine the effectiveness of tailoring postoperative thromboprophylaxis to the individual risk profile of patients undergoing craniotomy for primary malignant brain tumors.