Abstract
Background
Meningioma resection is associated with the risk of venous thromboembolism (VTE).
Objectives
To determine the incidence and risk factors for VTE following meningioma resection and VTE outcomes based on the type and timing of anticoagulation.
Methods
From 2011 to 2019, 901 consecutive patients underwent meningioma resection. We retrospectively evaluated the postoperative incidence of VTE and bleeding. For VTE, we determined the treatment strategy and rate of VTE complications and bleeding.
Results
Pharmacologic prophylaxis was administered to 665 (73.8%) patients. The cumulative incidence for total postoperative VTE was 8.7% (95% CI: 6.9%-10.6%), and for symptomatic VTE was 6.0% (95% CI: 4.6%-7.7%). A multivariable model identified the following independent predictors of symptomatic VTE: history of VTE, obesity, and lack of pharmacologic prophylaxis. Following postoperative VTE, 58 (74.3%) patients received therapeutic anticoagulation either initially (33.3%) or after a median delay of 23.5 days (41.0%). Symptomatic recurrent VTE occurred in 13 (16.6%) patients. Following VTE, the use of subtherapeutic anticoagulation was associated with a lower rate of total VTE extension than no anticoagulation (17.5% vs 42.9%, OR 0.28, 95% CI: 0.09–0.93). In total, 14 patients (1.6%) experienced clinically relevant bleeding: 4 received therapeutic anticoagulants, 8 received prophylactic anticoagulation, and 2 received no anticoagulation. Among patients with VTE, 4 (5.1%) experienced bleeding.
Conclusion
Recognition of risk factors for VTE following meningioma resection may help improve approaches to thromboprophylaxis. The management of postoperative VTE is highly variable, but most VTE patients are ultimately treated with therapeutic anticoagulants.
Keywords: anticoagulants, craniotomy, meningioma, pulmonary embolism, venous thromboembolism
Essentials
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What are the risk factors for and outcomes of thrombosis after meningioma resection?
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We analyzed consecutive patients undergoing meningioma resection.
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A history of blood clots, obesity, and no anticoagulant prophylaxis was associated with thrombosis.
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Following thrombosis, low-dose anticoagulants may help if full-dose anticoagulants cannot be used.
1. Introduction
Meningioma is the most common primary brain tumor in adults, and its management frequently involves neurosurgical resection. Most meningiomas are considered benign tumors, and patients tend to perform better than those with other types of brain tumors. Venous thromboembolism (VTE) is rare in patients with meningioma who have not undergone surgery [1]. However, the risk of VTE in the setting of surgical resection of meningioma has been reported to be between 2% and 8% [[2], [3], [4], [5], [6], [7], [8], [9]], similar to the risk associated with resection of malignant or metastatic brain tumors [[10], [11], [12]]. In patients undergoing craniotomy for meningioma resection, those who develop postoperative VTE have a higher risk of prolonged hospitalization and postoperative complications, including stroke, sepsis, unplanned intubation, readmission, and death [3,5].
Venous thromboembolism prophylaxis for patients undergoing craniotomy is not standardized and frequently debated [8,13,14]. Reasons for this include a lack of high-quality evidence evaluating the safety and efficacy of pharmacologic prophylaxis. Concern for intracranial hemorrhage (ICH) following skull base surgery may lead to highly variable prophylaxis strategies based on individual provider practice. Current guidelines recommend mechanical prophylaxis, with the addition of pharmacologic prophylaxis for patients at very high risk for thrombosis [14,15]. In patients who develop VTE, there are no guidelines and limited data to direct the use of anticoagulants or placement of inferior vena cava (IVC) filters in the setting of high bleeding risk following craniotomy [16].
Using a large cohort of consecutive patients from a high-volume meningioma resection practice, we aimed to determine the incidence and risk factors for VTE following meningioma surgery. We also describe postneurosurgical VTE management regarding the dose and timing of anticoagulation, IVC filter placement, and clinical outcomes, including bleeding and VTE extension and recurrence.
2. Methods
2.1. Data collection
We retrospectively reviewed the electronic medical record of 903 consecutive patients who underwent surgical resection of meningioma at Brigham and Women’s Hospital, a tertiary referral center in Boston, between June 2011 and June 2019. Two patients were excluded because surgical pathology was inconsistent with meningioma, leaving a total of 901 consecutive patients with no further exclusions. Overall, 233 of these patients have been described in a previous study [17]. Patient demographics, comorbidities, and medications were recorded. The duration of surgery was summed for patients with a planned 2-stage procedure and was missing for 368 patients. There was no other missing data. Tumor volume (divided into quartiles) and extent of resection were determined using manual contouring of pre-and postoperative T1-weighted MRI images in Brainlab Cranial Software (Westchester). Tumor location was divided into 5 groups: lateral convexity, midline convexity, lateral skull base, midline skull base, and other.
All patients were followed up for at least 90 days after meningioma resection. All patients had follow-ups at 3 months postoperatively, per the standard protocol at Brigham and Women’s Hospital. Outcomes were VTE or major or clinically relevant nonmajor bleeding occurring within 90 days of surgery. All patients diagnosed with VTE at an outside facility were transferred to Brigham and Women’s Hospital for further management. The diagnosis of postoperative deep vein thrombosis (DVT) was performed or confirmed by compression venous ultrasound performed by sonographers from the Brigham and Women’s Hospital Vascular Laboratory, which is accredited by the Intersocietal Accreditation Commission. Pulmonary embolism (PE) was detected by axial multidetector computed tomography angiography using spiral acquisition and interpreted by a radiologist, either at Brigham and Women’s Hospital or an outside referring hospital. For PE diagnosed at an outside facility, images and radiology reports were reviewed by a staff vascular medicine physician. The timing, location, and whether there was an extension or recurrence of DVT and PE were obtained by reviewing the medical records. Symptomatic VTE events were those with clear documentation of signs and/or symptoms consistent with VTE prior to the diagnostic study (eg, leg edema or pain for DVT, shortness of breath, tachycardia, or hypoxia for PE). VTE diagnosis without documented signs or symptoms of VTE was designated as asymptomatic. All cases of VTE were separately adjudicated by a cardiovascular physician who was blinded to the prophylaxis status of the patient (A.A.S.). For VTE events, the management was determined by reviewing the medical records. The neurosurgical service did not use any clinical protocols or algorithms to dictate thromboprophylaxis practices or therapy for incident VTE. The treatment plan was recorded, including observation, placement of an IVC filter, and administration and dose of anticoagulants. In all patients who experienced a postoperative VTE, follow-up was extended for 90 days after VTE diagnosis. Among patients with VTE, outcomes included an extension of clot burden prior to administering anticoagulants, recurrent VTE, death, and clinically relevant bleeding.
Bleeding events were collected through a chart review. Individual patient records were reviewed to determine which patients experienced International Society of Hemostasis and Thrombosis (ISTH) major bleeding within the 90-day postoperative period and 90 days following the diagnosis and treatment of VTE [18]. All ICH events were adjudicated by a neurosurgeon who was blinded to the anticoagulation status of the patient (W.L.B.). Any episode of surgical or nonsurgical bleeding that did not meet the ISTH definition of major bleeding but required medical evaluation or intervention was designated as clinically relevant nonmajor bleeding [19].
Study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at Mass General Brigham. The study was approved by the Mass General Brigham Institutional Review Board, and informed consent was waived, given that the study was a medical records review.
2.2. Statistical analysis
Patient demographic and clinical information were univariately compared between the VTE and non-VTE groups. Chi-squared and Fisher’s exact tests were used to compare categorical variables. For univariable analysis, Cox proportional hazards regression was fitted for each variable separately to compute the unadjusted hazard ratio and 95% CI. Age, duration of surgery, and duration of hospitalization were analyzed as continuous variables. Stepwise selection was used for multivariable analysis to assess the inclusion of candidate variables in the model taken from the univariable analysis. A P value threshold of 0.4 in the univariable analysis was used to include variables in the model, and a P value threshold of 0.05 for multivariable analysis was used to remove variables from the model. Cox proportional hazards regression was fitted for selected variables to compute the adjusted hazard ratio, 95% CI, and P value. Fine-gray methods accounted for the competing risk of death for symptomatic VTE. All statistical analyses were performed using the SAS/STAT software (version 9.4, 2013) or GraphPad Prism (version 9.0; GraphPad Software).
3. Results
3.1. Patient demographics
A total of 901 consecutive patients were included. The mean age of the cohort was 56.7 years (range: 18-93 years), and 67.1% were female (Table 1). The most prevalent comorbidities were hypertension (38.6%) and hyperlipidemia (29.6%). Of the VTE risk factors that were evaluated, obesity (defined as a BMI > 30 kg/m2, 38.3%) and the presence of an indwelling catheter (14.4%) were the most common. A history of VTE was present in 6% of the patients. Prior to surgery, 17.3% of the patients received antiplatelet therapy, and 4.1% received therapeutic anticoagulants.
Table 1.
Patient demographics, clinical and tumor characteristics, VTE risk factors, and inpatient prophylaxis in VTE and non-VTE patients.
| 901 Total, N (%) |
823 non-VTE, N (%) |
78 VTE, N (%) |
54 VTE, symptomatic N (%) | |
|---|---|---|---|---|
| Demographics | ||||
| Age (yrs) | 56.7 ± 13.9 | 56.4 ± 13.9 | 60.2 ± 13.4 | 57.7 ± 14.1 |
| Sex (male) | 296 (32.9) | 265 (32.1) | 31 (39.7) | 19 (35.2) |
| Race/ethnicity | ||||
| White | 766 (85.0) | 708 (86.0) | 58 (74.4) | 40 (74.0) |
| Black | 48 (5.3) | 40 (4.9) | 8 (10.3) | 6 (11.1) |
| Asian | 21 (2.3) | 20 (2.4) | 1 (1.2) | 0 (0.0) |
| Hispanic | 20 (2.2) | 15 (1.8) | 5 (6.4) | 3 (5.6) |
| Other/unknown | 46 (5.1) | 40 (4.9) | 6 (7.7) | 2 (9.3) |
| Comorbidities | ||||
| Hypertension | 348 (38.6) | 309 (37.5) | 39 (49.4) | 28 (51.9) |
| Hyperlipidemia | 267 (29.6) | 241 (29.2) | 26 (32.9) | 16 (29.6) |
| Diabetes | 116 (12.9) | 106 (12.8) | 10 (12.6) | 8 (14.9) |
| Coronary artery/peripheral Artery disease | 51 (5.7) | 47 (5.7) | 4 (5.0) | 4 (7.4) |
| Atrial fibrillation/flutter | 41 (4.5) | 35 (4.3) | 4 (5.1) | 2 (3.7) |
| Stroke/transient ischemic attack | 31 (3.4) | 28 (3.4) | 3 (3.8) | 3 (5.6) |
| Renal insufficiency | 22 (2.4) | 17 (2.1) | 5 (6.3) | 4 (7.4) |
| Home antithrombotic therapy | ||||
| Antiplatelet therapy | 156 (17.3) | 139 (16.9) | 17 (21.5) | 9 (16.7) |
| Anticoagulation therapy | 37 (4.1) | 30 (3.6) | 7 (9.0%) | 6 (11.1) |
| VTE risk factors | ||||
| Obesity | 345 (38.3) | 305 (37.1) | 40 (50.6) | 29 (53.7) |
| Indwelling catheter | 130 (14.4) | 110 (13.4) | 20 (25.6) | 14 (25.9) |
| Current smoker | 57 (6.3) | 53 (6.5) | 4 (5.1) | 3 (5.6) |
| Prior VTE | 54 (6.0) | 40 (4.9) | 14 (17.7) | 12 (22.2) |
| Active cancer (non-meningioma) | 52 (5.8) | 48 (5.8) | 4 (5.1) | 3 (5.6) |
| Autoimmune disease | 51 (5.7) | 48 (5.8) | 3 (3.8) | 2 (3.7) |
| Antithrombotic prophylaxis | ||||
| Pharmacologic | 665 (73.8) | 626 (76.1) | 39 (50.0) | 25 (46.3) |
| Mechanical only | 236 (26.2) | 197 (23.9) | 39 (50.0) | 29 (53.7) |
| Duration of surgery (hrs)a | 5.9 ± 3.2 | 5.7 ± 3.0 | 7.6 ± 3.7 | 7.6 ± 4.0 |
| (mean ± SD) | ||||
| Duration of hospitalization (days) | 5.4 ± 4.1 | 5.3 ± 3.7 | 9.0 ± 6.9 | 9.1 ± 6.5 |
| (mean ± SD) | ||||
| Tumor grade I | 607 (67.4) | 551 (67.0) | 56 (71.8) | 38 (70.4) |
| Tumor grade II/III | 265 (29.4) | 245 (29.8) | 20 (25.6) | 15 (27.8) |
| Unknown tumor grade | 29 (3.2) | 27 (3.3) | 2 (2.6) | 1 (1.9) |
| Meningioma location | ||||
| Midline convexity | 152 (16.8) | 132 (16.0) | 20 (25.6) | 13 (24.0) |
| Midline skull base | 168 (18.6) | 151 (18.3) | 17 (21.8) | 13 (24.0) |
| Lateral skull Base | 198 (22.0) | 172 (20.9) | 26 (33.3) | 15 (27.8) |
| Lateral convexity | 249 (27.6) | 244 (29.6) | 5 (6.4) | 5 (9.3) |
| Other tumor location | 111 (12.3) | 105 (12.8) | 6 (7.7) | 6 (11.1) |
| Unknown location | 23 (2.6) | 19 (2.3) | 4 (5.1) | 2 (3.7) |
| Preoperative volume | ||||
| Quartile 1 | 217 (24.1) | 206 (25.0) | 11 (14.1) | 9 (16.7) |
| Quartile 2 | 218 (24.2) | 200 (24.3) | 18 (23.0) | 11 (20.4) |
| Quartile 3 | 219 (24.3) | 199 (24.2) | 20 (25.6) | 16 (29.6) |
| Quartile 4 | 215 (23.8) | 192 (23.3) | 23 (29.5) | 15 (27.8) |
| Unknown volume | 32 (3.6) | 26 (3.2) | 6 (7.7) | 3 (5.6) |
| Degree of resection | ||||
| Gross total resection | 638 (70.8) | 595 (72.3) | 43 (55.1) | 30 (55.6) |
| Near total resection | 74 (8.2) | 65 (7.9) | 9 (11.5) | 7 (13.0) |
| Subtotal resection | 153 (17.0) | 133 (16.2) | 20 (25.6) | 14 (25.9) |
| Unknown resection | 36 (4.0) | 30 (3.6) | 6 (7.7) | 3 (5.6) |
Duration of surgery data were missing for 368 patients. Values are numbers and percentages unless otherwise specified.
VTE, venous thromboembolism.
Postoperatively, all patients received mechanical VTE prophylaxis in the form of intermittent pneumatic compression devices, and 665 (73.8%) received inpatient pharmacologic prophylaxis with unfractionated heparin (5000 units subcutaneous every 8 hours) until hospital discharge (Table 1). Prophylaxis for VTE (pharmacologic plus mechanical versus mechanical alone) was administered according to the preference of the neurosurgeon. There was no prespecified protocol for postsurgical VTE prophylaxis. A comparison of baseline characteristics between those receiving and not receiving pharmacologic prophylaxis is presented in Supplementary Table 1. The mean duration of surgery, as defined from the initiation of anesthesia to patient awakening, was 5.9 hours. All patients had follow-ups at 3 months postoperatively, and no patients were lost to follow-up. Three patients died from non-VTE- or non-bleeding-related causes prior to postoperative (POD) 90 and were censored.
3.2. Venous thromboembolism incidence
Over the 90-day follow-up period, the cumulative incidence for total VTE was 8.7% (95% CI: 6.9%-10.6%). The cumulative incidence of symptomatic VTE, defined as VTE where documented signs or symptoms prompted diagnostic testing, was 6.0% (95% CI: 4.6%-7.7%), considering the competing risk of death in both cases (Table 2 and Figure 1). For 24 VTE events (30.8%), all of which were DVTs, we were not able to determine from the medical record whether symptoms were present prior to VTE diagnosis. VTE was diagnosed at a median of 7.5 days postoperatively (25%-75% interquartile range [IQR]: 2-19.5 days). Among patients receiving mechanical VTE prophylaxis only, VTE (n = 39) was diagnosed at a median of 2 days postoperatively (25%-75% IQR: 1-7 days), whereas patients receiving pharmacologic VTE prophylaxis, VTE (n = 39) was diagnosed at a median of 14 days postoperatively (25-75% IQR: 8-31 days, Figure 1). Among the 78 patients with VTE, 45 (57.7%) had DVT alone, 20 (25.6%) had PE with concomitant DVT, and 13 (16.7%) had PE alone (Table 2). Of the 45 patients who developed DVT alone, the majority had an initial distal lower extremity DVT (n = 30, 66.7%), whereas the remainder had a proximal lower extremity (n = 13, 28.9%) or upper extremity DVT (n = 2, 4.4%). However, 12 out of 30 (40%) distal DVT progressed to proximal DVT (see VTE extension and recurrence). Among the 24 asymptomatic DVT, 7 were proximal DVT, 6 progressed to a proximal vein, and 1 was associated with a subsequent PE.
Table 2.
Postoperative VTE incidence and classification.
|
N = 901 total patients |
N (% all patients, % of patients with VTE) |
|---|---|
| VTE cases | |
| Total VTE | 78 (8.7, 100) |
| Symptomatic PE or DVT | 54 (6.0, 69.2) |
| Asymptomatic DVT | 24 (2.7, 30.8) |
| PE alone | 13 (1.4, 16.7) |
| Initial PE with DVT | 15 (1.7, 19.2) |
| Initial DVT progressing to PE | 5 (0.6, 6.4) |
| DVT alone | 45 (5.0, 57.7) |
| Initial proximal vein DVT | 13 (1.4, 16.7) |
| Distal DVT progressing to proximal DVT | 12 (1.3, 15.4) |
| Distal vein DVT only | 18 (2.0, 23.1) |
| Upper extremity DVT only | 2 (0.2, 2.6) |
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.
Figure 1.
Time-to-event curves for total VTE (A), total VTE by the method of prophylaxis (B), and symptomatic VTE by the method of prophylaxis (C). Mech, mechanical; Pharm, pharmacologic; prophy, prophylaxis; VTE, venous thromboembolism.
3.3. Venous thromboembolism predictors
We analyzed covariates related to postoperative VTE in univariable analysis for symptomatic VTE. In our unadjusted model, the use of pharmacologic prophylaxis, non-White/non-Asian race, hypertension, renal insufficiency, home anticoagulation therapy, obesity, presence of an indwelling catheter, prior history of VTE, the duration of surgery, tumor location in the lateral convexity, and subtotal tumor resection was associated with the development of VTE after meningioma resection on univariable analysis (Table 3). Multivariable analysis (Table 4 and Supplementary Table 2) revealed the following independent risk factors for VTE: history of VTE (HR: 5.03, 95% CI: 2.65-9.54), obesity (HR: 1.87, 95% CI: 1.09-3.21), and inpatient pharmacologic prophylaxis (HR: 0.29, 95% CI: 0.17-0.50). The duration of surgery was not included in the multivariable model because data were missing for 368 patients.
Table 3.
Unadjusted hazard ratios for predictors of VTE events in univariable analysis.
| Hazard ratio | 95% CI | |
|---|---|---|
| Demographics | ||
| Age (y) | 1.01 | 0.99-1.03 |
| Sex (male) | 1.11 | 0.64-1.94 |
| Non-Asian, non-White | 2.02 | 1.10-3.69 |
| Comorbidities | ||
| Hypertension | 1.73 | 1.02-2.95 |
| Hyperlipidemia | 0.99 | 0.56-1.78 |
| Diabetes | 1.17 | 0.56-2.47 |
| Coronary/peripheral artery disease | 1.33 | 0.49-3.6 |
| Atrial fibrillation/flutter | 0.82 | 0.20-3.34 |
| Stroke/transient ischemic attack | 1.69 | 0.53-5.38 |
| Renal insufficiency | 3.49 | 1.25-9.78 |
| Home antithrombotic therapy | ||
| Antiplatelet therapy | 0.95 | 0.47-1.93 |
| Anticoagulation therapy | 3.10 | 1.33-7.22 |
| VTE risk factors | ||
| Obesity | 1.91 | 1.12-3.25 |
| Indwelling catheter | 2.11 | 1.15-3.84 |
| Current smoker | 0.87 | 0.27-2.76 |
| Prior VTE | 4.95 | 2.61-9.36 |
| Active cancer (non-meningioma) | 0.95 | 0.30-3.01 |
| Autoimmune disease | 0.63 | 0.16-2.53 |
| Antithrombotic prophylaxis | ||
| Pharmacologic | 0.29 | 0.17-0.49 |
| Mechanical only | 3.47 | 2.04-5.90 |
| Duration of surgery (h)a | 1.16 | 1.06-1.26 |
| Duration of hospitalization (d)b | 1.01 | 0.93-1.10 |
| Tumor grade: grade 2/3 vs grade 1 | 0.89 | 0.49-1.62 |
| Meningioma location | ||
| Midline convexity vs midline skull base | 0.89 | 0.42-1.91 |
| Lateral skull base vs midline skull base | 0.88 | 0.42-1.85 |
| Lateral convexity vs midline skull base | 0.23 | 0.08-0.64 |
| Other tumor location vs midline skull base | 0.62 | 0.24-1.63 |
| Preoperative volume | ||
| Quartile 2 vs quartile 1 | 1.22 | 0.51-2.93 |
| Quartile 3 vs quartile 1 | 1.81 | 0.80-4.10 |
| Quartile 4 vs quartile 1 | 1.69 | 0.74-3.85 |
| Degree of resection | ||
| Near total resection vs gross total resection | 2.05 | 0.91-4.62 |
| Subtotal resection vs gross total resection | 2.01 | 1.07-3.80 |
Duration of surgery data were missing for 368 patients.
Duration of hospitalization was censored at the time of VTE diagnosis. VTE, venous thromboembolism.
Table 4.
Adjusted hazard ratios for predictors of VTE events in multivariable analysis.
| Risk factor | Hazard ratio | 95% CI |
|---|---|---|
| History of VTE | 5.03 | 2.65-9.54 |
| Obesity | 1.87 | 1.09-3.21 |
| Pharmacologic prophylaxis | 0.29 | 0.17-0.50 |
VTE, venous thromboembolism.
3.4. Management of venous thromboembolism
Management approaches for VTE following meningioma resection are summarized in Figure 2. Among the 78 patients with VTE, 58 (74.3%) ultimately received therapeutic anticoagulants following VTE diagnosis. Therapeutic anticoagulation was administered directly following VTE diagnosis or after an extended delay. Twenty-six patients (33.3% of the total VTE cases) received therapeutic anticoagulants promptly after VTE diagnosis, defined as immediately following VTE diagnosis in 22 patients or after a delay of 1 to 4 days (median 2 days) in 4 patients. The timing of this delay corresponded to the initiation of therapeutic anticoagulation of median POD 14 (25%-75% IQR: 8.5-32 days) in these 26 patients. Six of these 26 patients were started on therapeutic anticoagulants within 7 days postoperatively. In another 32 patients (41% of total VTE cases), the initiation of therapeutic anticoagulation was delayed for a median of 23.5 days (25%-75% IQR: 8.5-32 days) following VTE diagnosis corresponding to median POD 29.5 (25%-75% IQR 20.5-44.25). During this delay interval, only one patient was administered subtherapeutic (prophylactic-dose) anticoagulation with unfractionated heparin (5000 units every 8 hours). The most frequently prescribed therapeutic anticoagulation strategies were unfractionated heparin bridging to warfarin (29 patients, 50.0%) or apixaban (19 patients, 32.8%). Eight patients (10.3%) with VTE were treated with subtherapeutic anticoagulation only. Twelve patients (15.4%) received no anticoagulants.
Figure 2.
Management of VTE following meningioma resection. A flow diagram based on the anticoagulation strategy for VTE cases. In all cases, STAC was unfractionated heparin, 5000 units every 8 hours. The number of patients who underwent placement of an IVC filter is listed for each group. The type of therapeutic anticoagulation selected is listed. AC, anticoagulation; IVC, inferior vena cava; STAC, subtherapeutic anticoagulation; TAC, therapeutic anticoagulation. ∗Prompt TAC is defined as anticoagulation immediately upon diagnosis or after a delay of 1 to 4 days. In 6 patients, TAC was started within 7 days postoperatively.
Following VTE, 36 (46.2%) patients in total underwent placement of an IVC filter (Figure 2). IVC filter placement was performed in 26 out of 32 patients with VTE who were initially treated with subtherapeutic anticoagulation but ultimately were treated with therapeutic anticoagulation after a delay. Four patients received an IVC filter in addition to immediate therapeutic anticoagulation following VTE diagnosis. Three patients had an IVC filter placed and received subtherapeutic anticoagulation only, and 3 patients underwent IVC filter placement and received no anticoagulant. We confirmed the removal of 24 (66.6%) IVC filters after a mean of 5 ± 3.4 months.
3.5. Venous thromboembolism extension, recurrence, and death
VTE recurrence or extension events are outlined in Figure 3. Among patients with VTE, 18 (23.0%) had a recurrent VTE or extension of DVT: 6 (7.7%) had new or worsened PE, and 12 (15.4%) had an extension of distal DVT to proximal DVT or new bilateral DVT. Five of these DVT events were an asymptomatic proximal extension of DVT or asymptomatic detection of new bilateral DVT, and therefore symptomatic recurrent VTE occurred in 13 (16.6%, Figure 3). Two of 26 patients (7.7%) receiving therapeutic anticoagulants experienced symptomatic VTE extension compared with 11 of 52 patients (21.2%) not receiving therapeutic anticoagulants (OR 0.31, 95% CI: 0.07-1.3). One of the 2 patients receiving therapeutic anticoagulants experienced a new PE while on apixaban. The other patient presented with a massive PE as the initial VTE event after hospital discharge on POD 17. The patient received anticoagulation with unfractionated heparin and emergency systemic thrombolysis with alteplase but died.
Figure 3.
Flow diagram of VTE recurrence or extension. VTE progression is grouped by the type of event (PE, symptomatic or asymptomatic DVT) and the management the patient received prior to VTE progression. AC, anticoagulation; DVT, deep vein thrombosis; IVC, inferior vena cava; PE, pulmonary embolism; STAC, subtherapeutic anticoagulation; TAC, therapeutic anticoagulation; VTE, venous thromboembolism.
Treatment of VTE with subtherapeutic (prophylactic-dose) anticoagulation was associated with a lower incidence of total VTE extension or recurrence than observation alone. Seven of 40 patients receiving subtherapeutic anticoagulants (17.5%) experienced recurrent VTE, compared to 9 of 21 (42.9%) patients who were observed without anticoagulation (OR 0.28, 95% CI: 0.09-0.93). Among the 36 patients who underwent placement of an IVC filter, 3 (8.3%) suffered PE despite the presence of the filter. Five patients (13.9%) had an extension of DVT following IVC filter placement. Therapeutic anticoagulation was ultimately started in 16 of the 17 surviving patients with VTE extension or recurrence after a median interval of 26.1 days (25%-75% IQR: 8.5-32 days) following VTE diagnosis, and one patient was maintained on subtherapeutic anticoagulation only. None of the patients who started on therapeutic anticoagulants following VTE extension or recurrence experienced recurrent VTE or bleeding.
3.6. Bleeding events
Postoperative ICH occurred in 6 (0.90%) patients receiving pharmacologic prophylaxis and in 2 (0.85%) patients receiving mechanical prophylaxis only (OR 1.07, 95% CI 0.26-5.2). Bleeding required a return to the OR for 2 patients receiving pharmacologic prophylaxis and for 1 patient receiving mechanical prophylaxis only. This later patient ultimately died from multiple surgical complications. ISTH clinically relevant nonmajor bleeding from the wound site occurred in 1 (0.2%) patient receiving prophylactic anticoagulation and in 0 patients receiving mechanical prophylaxis only. One patient with a history of VTE on long-term therapeutic anticoagulation suffered a fatal epidural hematoma on POD 14 while receiving therapeutic unfractionated heparin infusion, which was resumed on POD 10.
Among patients diagnosed with VTE, bleeding occurred in 4 patients (5.1%). Two (2.6%) patients experienced postoperative ICH that was monitored but did not require a return to the OR. One patient experienced subarachnoid hemorrhage 29 days after therapeutic apixaban was started (POD 116). The other patient experienced a subdural hematoma while receiving subtherapeutic anticoagulation on POD 80, 77 days after initiating anticoagulation. One patient receiving therapeutic warfarin developed epistaxis requiring intervention on POD 39, 28 days after initiating anticoagulation. Another patient receiving therapeutic heparin developed significant hematuria on POD 15, 3 days after initiating anticoagulation.
4. Discussion
Venous thromboembolism is a common and potentially serious complication following meningioma resection. In one study, VTE was the second most frequent adverse event following brain tumor resection and the third most common cause of readmission [20]. We observed a 6.0% cumulative incidence of symptomatic postoperative VTE and an 8.7% cumulative incidence of total postoperative VTE within 90 days in a cohort of 901 consecutive patients undergoing meningioma resection. Independent predictors of postoperative VTE were a history of VTE, obesity, and lack of inpatient pharmacologic prophylaxis. The use of prophylactic anticoagulation was not associated with an increased incidence of intra- or extracranial bleeding. Most patients with VTE (74.3%) were treated with therapeutic anticoagulation, but in more than half of these cases, anticoagulation was delayed for a median of 3 weeks.
In many cases, therapeutic anticoagulation was not initiated until there was a proximal extension of VTE or the development of symptomatic PE. During the delay before the initiation of therapeutic anticoagulation, patients with VTE were often treated with subtherapeutic (prophylactic-dose) anticoagulation. This strategy appeared beneficial, as treating VTE with subtherapeutic anticoagulation was associated with a lower rate of VTE complications than no anticoagulation. Among the 57 patients with VTE managed with therapeutic anticoagulation, 4 bleeding events occurred (2 ICH not requiring a return to the OR and 2 extracranial, nonmajor bleeding), representing 5.3% of all patients receiving therapeutic anticoagulation.
Among patients undergoing brain tumor resection, there is little standardization and frequent debate about the optimal strategies to prevent VTE and major bleeding. There is even more variability and lack of guidance regarding the management of VTE diagnosed following craniotomy. Among our cohort, treatment was largely determined on a case-by-case basis by the preference of the neurosurgeon. Frequently, but not universally, postneurosurgical VTE was co-managed in consultation with vascular medicine, who could help risk-stratify VTE and provide recommendations on anticoagulation strategies and the use of adjunctive treatments such as IVC filter placement.
The clinical dilemma of post-craniotomy VTE is the risk of hemodynamically significant/fatal PE or severe DVT versus the risk of debilitating/fatal ICH following prophylactic or therapeutic anticoagulation. In practice, concern regarding the use of anticoagulants often leads to monitoring with serial ultrasound of thrombotic events deemed low-risk, such as isolated calf-vein DVT. Treatment with therapeutic anticoagulation and/or IVC filter is then reserved for proximal DVT and/or PE. While commonly used, the monitoring strategy has not been studied and certainly carries risks. Indeed, in our cohort, 12 out of 30 calf-vein DVTs (30%) progressed proximally, including 3 PE (10%). Data from current practice suggest that postneurosurgical patients who develop PE may be more likely to die from PE than from ICH, despite the use of anticoagulants [21]. Furthermore, most patients with symptomatic PE do not have preceding symptoms of DVT [22]. Therefore, it seems appropriate to emphasize strategies for VTE prevention.
Consensus guidelines, including the American Society of Hematology, recommend against routine pharmacologic VTE prophylaxis in neurosurgery patients [14,15]. Nevertheless, our findings are consistent with a growing body of literature suggesting that pharmacologic prophylaxis with unfractionated or low-molecular-weight heparin is a safe and effective VTE prevention strategy following brain tumor resection [2,4,7,9,12,[23], [24], [25], [26]]. Post-craniotomy patients are at high risk for bleeding, and therapeutic anticoagulation is often contraindicated, at least temporarily. Subtherapeutic anticoagulation may reduce the risk of VTE extension until it is safe to administer full therapeutic anticoagulation. Delayed or insufficient anticoagulation, common in our cohort, is a risk factor for post-thrombotic syndrome, a debilitating form of chronic venous insufficiency [27].
Previous investigations have reported a frequency of symptomatic VTE following meningioma resection of approximately 2% to 8% [[2], [3], [4], [5], [6], [7], [8], [9]]. In some prior studies, higher rates of postoperative VTE are likely a result of VTE screening in asymptomatic patients [11,28]. Screening for DVT following meningioma resection may be a common practice [8]. In our cohort, some patients were diagnosed with DVT following a postoperative ultrasound without clear documentation of DVT symptoms. Among these potentially clinically silent VTEs, one-third were proximal events, and another third were calf DVT that progressed to proximal DVT or PE. Asymptomatic DVT is associated with the development of post-thrombotic syndrome [29] and, at least among medical patients, increased all-cause mortality [30,31].
We identified similar risk factors for VTE following meningioma resection as prior studies [6,8,9,12]. Possible mechanisms underlying these observations include a combination of tumor- and patient-related factors, as well as systemic responses to surgery. Postoperative ICH occurred in 1.1% of patients, was not associated with pharmacologic prophylaxis status, and required a return to the OR in only 3 (0.3%) cases. These bleeding rates are lower than other case series of meningioma resection, which report postoperative ICH rates of 2% to 4% [[2], [3], [4], [5], [6], [7], [8], [9]].
Limited studies have assessed the safety of therapeutic anticoagulants to treat VTE following craniotomy. Scheller et al. [32] reported no bleeding events in 42 patients who developed VTE following brain tumor resection and were ultimately treated with therapeutic unfractionated heparin or enoxaparin on median POD 12. Riviere-cazaux et al. [20] recently analyzed a cohort of 18 patients who developed VTE post-craniotomy and received therapeutic anticoagulation within 7 days of surgery. Most patients were treated with unfractionated heparin and transitioned to either warfarin, enoxaparin, or apixaban. One patient (5.6%) developed ICH requiring hematoma evacuation [20]. De Melo Junior et al. studied 53 patients who developed VTE following intracranial neurosurgery and were started on therapeutic anticoagulation within 30 days [33]. Patients treated with warfarin (53.7%) experienced a higher rate of ICH (13.8%), 2 of which were fatal, compared with zero ICH events among 38.9% treated with a direct oral anticoagulant or 7.4% treated with LMWH [33]. This distribution of therapeutic anticoagulation regimens was very similar to that of our cohort. In our study, there was only one ICH event in a patient receiving therapeutic apixaban for VTE. The one fatal bleed in our cohort was a nontraumatic epidural hematoma that occurred in a patient on long-term anticoagulation in whom therapeutic anticoagulation was resumed on POD 10.
A large fraction (46.2%) of patients diagnosed with VTE in our cohort underwent placement of an IVC filter, rates much higher than that observed in similar studies of post-craniotomy VTE [20,21,34]. One explanation for this finding may be the relatively longer delay on average (3 weeks) before initiating therapeutic anticoagulants. However, 4 patients underwent IVC filter placement concurrent with initiating therapeutic anticoagulants, and 7 received an IVC filter for an isolated distal DVT. Guidelines do not typically recommend IVC filter placement in these scenarios [35]. We observed recurrent DVT or PE in 22.2% of patients after placement of the IVC filter, a reminder that these devices carry complications and may not accomplish their intended purpose of preventing PE. Furthermore, we could only confirm that 66.6% of the filters were subsequently removed.
Limitations of our study include its retrospective, single-center design and lack of standardization for managing VTE following neurosurgery. Our study is not specifically designed to evaluate the efficacy and safety of pharmacologic VTE prophylaxis. The modality of VTE prophylaxis was not randomly assigned, and therefore, the decision to use pharmacologic versus mechanical prophylaxis may have been based, at least in part, on a perceived risk of bleeding or thrombosis. The threshold to perform a postoperative venous ultrasound may have been lower in patients who did not receive pharmacologic prophylaxis, resulting in ascertainment bias and more DVT diagnoses in this group. We cannot rule out the possibility that a VTE or bleeding event occurred within 90 days postoperatively but was not captured in our medical records. However, given the concern about bleeding following neurosurgery, it is highly likely that a diagnosed VTE or bleeding episode would be reflected in the medical record reviewed at follow-up if it occurred within 90 days of craniotomy. Likewise, 100% follow-up of this cohort will likely provide an additional safeguard against missing events. Due to the relatively lower rates of intracranial hemorrhage in our study, it is difficult to compare our findings regarding the safety of prophylactic or therapeutic anticoagulation to studies from other centers and neurosurgical populations. Finally, patients with VTE not receiving therapeutic anticoagulation may have been more likely to undergo repeat imaging if they developed new symptoms, resulting in ascertainment bias and an increased likelihood of detecting recurrent VTE.
The strengths of our study are that, to our knowledge, it is the largest single institution-based consecutive-patient analysis of VTE following meningioma resection. It is also one of the only investigations to specifically assess VTE treatment approaches and outcomes in this population, regardless of whether patients received early therapeutic anticoagulation. We assess the efficacy and safety of initially using subtherapeutic anticoagulation to manage VTE following craniotomy, which appears to be a common clinical practice but has not been studied in terms of VTE outcomes [20,21].
Multi-institutional studies that evaluate practice patterns regarding prophylaxis and management of postneurosurgical VTE would provide further insight into this challenging clinical scenario. The inability of established VTE risk prediction models, such as the Khorana Score, to assess risk in this population highlights the need for specifically validated models [36]. Given the high number of patients who experience a significant delay in initiating therapeutic anticoagulation, the incidence of post-thrombotic syndrome should be investigated in larger cohorts of postneurosurgical VTE.
5. Conclusion
VTE is common following meningioma resection, despite the use of prophylactic anticoagulation. Most patients who develop postoperative VTE are ultimately treated with therapeutic anticoagulants, and VTE outcomes are favorable. Among patients with VTE and a contraindication to therapeutic anticoagulation, subtherapeutic anticoagulation may reduce the risk of VTE extension. In patients undergoing meningioma resection, prospective studies investigating novel methods of preoperative VTE risk assessment, straightforward VTE thromboprophylaxis protocols and guidelines for an effective and safe treatment for postsurgical VTE are needed.
Acknowledgments
Funding
This work was supported by the NHLBIK08HL161259 and John S. LaDue Memorial Fellowship (A.A.S.), Brigham Research Institute Precision Medicine Award (W.L.B.), and NHLBIK23HL150290 (E.A.S.).
Author contributions
A.A.S., U.C., W.L.B., G.P., and S.Z.G. designed the study. S.R., U.C., and A.A.S. performed the primary chart review. A.A.S., U.C., and W.L.B. adjudicated thrombotic, bleeding, and surgical outcomes. S.T., S.L., and E.A.S. performed the statistical analysis. All authors participated in writing the paper and approved the final version of the manuscript. All authors had access to all of the data used in this study.
Relationship Disclosure
S.Z.G. has received research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, the National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute, and consulting fees from Bayer, Agile, Boston Scientific, and Boehringer Ingelheim. G.P. has received research grant support from Boston Scientific, Bayer, Bristol Myers Squibb/Pfizer Alliance, Portola, Amgen, and Janssen, and consulting fees from Amgen, Pfizer, and Boston Scientific.
Footnotes
Handling Editor: Dr Lana Antoinette Castellucci
The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2023.100121
Supporting Information
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