Intracerebral hemorrhage risk in glioma patients taking direct oral anticoagulants as compared with low molecular weight heparin

Abstract

Abstract

BackgroundGlioma patients may require long-term anticoagulation for comorbidities, including arrhythmias or venous thromboembolism (VTE). While direct oral anticoagulants (DOACs) have demonstrated safety in general cancer populations, safety data for glioma patients remains limited. The aim of this study was to assess intracerebral hemorrhage (ICH) risk with DOAC compared to low molecular weight heparin (LMWH) in glioma patients.

Methods

We reviewed adult patients with primary glioma who received DOAC and/or LMWH for at least 10 days between 2008 and 2023 across Cleveland Clinic Health System hospitals. ICH rates and severity were compared between treatment groups.

Results

Among 277 patients (147 DOAC, 130 LMWH), median time from tumor diagnosis to first VTE was 70 days, with 32% experiencing VTE within six months of glioma diagnosis. Of these, 74% had glioblastoma. No statistically significant difference in ICH risk was found between DOAC and LMWH groups (P = .3) or across tumor grades (P = .6). Six ICH events occurred: three trace/minor, one subdural, and two major/fatal (both in LMWH patients). Five events occurred in glioblastoma patients and one in a patient with oligodendroglioma.

Conclusions

This observational study suggests DOACs are relatively safe in glioma patients given the low ICH risk. While most ICH events occurred in glioblastoma patients, no significant difference in risk was found across tumor grades. Prospective studies will establish anticoagulation risks in this population.

Key Points.

• Patients with glioma have a high risk of VTE and ICH

• Risk of ICH with DOAC is not well characterized, particularly for low-grade gliomas

• There was no difference in ICH risk between DOAC and LMWH nor across glioma tumor grades

Importance of the Study

Anticoagulation choice requires careful consideration in patients with glioma due to high rates of VTE juxtaposed by high risk of ICH, but there is limited safety data in this population, particularly in low-grade gliomas. Our findings contribute evidence supporting safe use of DOACs in glioma patients and will inform future prospective studies.

Patients with primary brain tumors (PBT) have a 20%-30% risk of venous thromboembolism (VTE) through unclear mechanisms, contributing to significant morbidity, mortality, and hospitalizations.^1-3 Glioblastoma (GBM), the most common PBT in adults, carries a 30% annual VTE risk.^1,4-6 This is juxtaposed by the relatively high (5%-8%) risk of spontaneous intracranial hemorrhage (ICH) in patients with GBM.^1,7,8 The increased spontaneous ICH risk in GBM is attributed to the production of tumor-related angiogenic mediators, such as vascular endothelial growth factor, and secretion of matrix metalloproteinase.⁵ Anticoagulation in brain tumor patients thus poses two divergent concerns: recurrent VTE or cardioembolic stroke without effective anticoagulation versus potentially severe intracranial hemorrhage with treatment. Further study of anticoagulation agents and choice is warranted to assure patient safety, especially among those with low-grade gliomas, where data are limited.⁹

Historically, patients with PBT and VTE received warfarin despite the potential risks of ICH. Warfarin poses additional stressors on patients, such as frequent monitoring and international normalized ratio (INR) fluctuations,¹⁰ leading to patients being outside of therapeutic anticoagulation range one-third of the time in US clinical practice.¹¹ As a result, the recommended anticoagulation choice for cancer associated thrombosis (CAT) over the past decade, including in glioma patients, has been low molecular weight heparin (LMWH).^12,13 The use of LMWH is supported by multiple trials, including a 2003 clinical trial of 676 adult cancer patients (27 with brain tumors) by Lee and colleagues that demonstrated a lower VTE recurrence risk with LMWH than with a warfarin derivative (hazard ratio = 0.48; P = .002).^14,15 A 2018 systematic review of five randomized control trials for VTE treatment in cancer patients found that LMWH likely reduces recurrent VTE risk to a greater extent than vitamin K antagonists, such as warfarin (RR 0.58, 95% CI 0.43-0.77).¹⁶ However, LMWH is associated with high costs and poor patient adherence due to daily subcutaneous injections and regular blood test monitoring.¹³

More recently, direct oral anticoagulants (DOACs) were approved for VTE in cancer patients based on several randomized controlled trials that compared DOAC versus LWMH safety (Table 1).^17-21 Current literature suggests that DOACs are non-inferior to LMWH in terms of recurrent VTE risk, but may be associated with increased risk of bleeding, especially in patients with gastrointestinal cancers.^12,20,22,23 However, most studies either excluded or had limited representation of brain tumor patients. Four clinical trials included brain tumor subgroups, comprising only 0.7%, 1.5%, 2.7%, and 6.8% of their study populations.^17,19,21,24 Limited retrospective studies comparing DOAC versus LMWH in brain tumor patients have shown no significant bleeding risk between treatment groups. In these studies, the cumulative incidence (CI) of bleeding with DOACs was often lower than with LMWH (Table 2).^25-28

Table 1.

Randomized controlled trials comparing DOACs and LMWH among cancer patients

Study name author	Year	Primary outcome	Sample size	Study type	Major findings
Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism Raskob et al.	2018	12-month recurrence of VTE	1046	RCT	Edoxaban was non-inferior to subcutaneous Dalteparin when measuring incidence of recurrent VTE for 12 months (RD −3.4 %; 95% CI, −7.0 to 0.2) Rate of major bleeding was higher among Edoxaban than with Dalteparin (RD 2.9% ; 95% CI, 0.1 to 5.6)
Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis Li et al.	2018	6-month recurrence of VTE	725	Meta-analysis of 2 RCTs	DOACs had a lower 6-month recurrence of VTE (42/725) than LMWH (64/727) (RR: 0.65 (0.42-1.01)). DOACs had more major bleeding (40/725) compared to LMWH (23/727) (RR 1.74 (1.05-2.88).
Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials Frere et al.	2022	recurrent VTE risk	3690	Meta- analysis of 6 RCTs	Patients receiving DOACs had significantly lower risk of recurrent VTE events (RR, 0.67 [95% CI, 0.52–0.84]) DOACs had a significant increase in clinically relevant non-major bleeding (RR, 1.66 [95% CI, 1.31-2.09]) compared to LMWH
Efficacy and safety of direct oral anticoagulants for secondary prevention of cancer associated thrombosis: a meta-analysis of randomized controlled trials Desai et al.	2020	recurrent VTE risk	4193	Meta-analysis of 10 RCTs	participants treated with DOACs had lower recurrent VTE risk compared to LMWH (RR 0.57; 95% CI 0.40-0.83; P = .003) Compared to LMWH, DOACs showed no difference in major bleeding risk (RR 1.31; 95% CI 0.78-2.18; P = .31) DOACs had a higher risk of clinically relevant non-major bleeding (CRNMB) (RR 1.60; 95% CI 1.13-2.26; P = .008)

Table 2.

Retrospective studies comparing risk of DOAC versus LMWH in brain tumor patients

Study name author	Year	Primary outcome	Sample size	Study type	Major findings
Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors Carney et al.	2019	Risk of ICH	67 patients with primary brain tumor	Retrospective cohort study	There were no major ICH events in the DOAC group and eight in the LMWH group (12-month cumulative incidence of 0% versus 18.2%; 95% CI, 8.4-31.0; P=.049). the cumulative incidence of any ICH was 0% in patients receiving DOACs (N = 41) and 36.8% (95% confidence interval [CI], 22.3%-51.3%) in those treated with LMWH (N = 131)
Intracranial hemorrhage with direct oral anticoagulants in patients with brain metastases Leader et al.	2020	12-month cumulative incidence of major ICH	96 patients with brain metastases	Retrospective cohort study	12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.09-2.21) when anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC- and LMWH- treated patients (HR, 0.98; 95% CI, 0.28-3.40)
Safety of Direct Oral Anticoagulants in Central Nervous System Malignancies Swart and Drappatz	2021	Rate of ICH	125 patients with brain tumors	Retrospective cohort study	rate of major bleeding was 26% in the LMWH group versus 9.6% in the DOAC group rate of ICH was 15% in the LMWH group versus 5.8% in the DOAC group (P = .09)
Direct oral anticoagulants or low-molecular-weight heparins for venous thromboembolism in patients with brain tumors Lee et al.	2021	6-month cumulative incidence of ICH	111 patients with primary or metastatic brain tumor	Retrospective cohort study	6-month cumulative incidence of intracranial hemorrhage was 4.3% (95% CI, 0.74–13.2%) in the DOAC group, compared to 5.9% (95% CI, 1.5–14.9%) in the LMWH group (p=0.61)
Comparison of direct oral anticoagulants versus low-molecular-weight heparin in primary and metastatic brain cancers: a meta-analysis and systematic review Iyenger et al.	2023	Risk of ICH	1638 patients with primary or metastatic brain cancer	Meta analysis and systematic review of 10 retrospective studies	in patients with metastatic brain cancer, there was no difference in the risk of ICH with the type of anticoagulation (RR, 1.05; 95% CI, 0.71-1.56; P = .80; I2= 0%)

Current (2023) American Society of Clinical Oncology (ASCO) guidelines for long-term anticoagulation in cancer patients recommend LMWH, apixaban, edoxaban, or rivaroxaban.²⁹ ASCO guidelines recommend that patients with primary or metastatic central nervous system (CNS) malignancies receive anticoagulation similar to other cancer patients, though this recommendation is based on expert consensus as opposed to evidence from clinical trials.²⁹ In contemporary clinical practice, patients with primary and metastatic brain tumors are commonly treated with DOACs for thromboembolic events.

DOACs may be a valuable anticoagulation choice for brain tumor patients, but ICH rates and severity in PBT are not well characterized, particularly for low-grade gliomas. In this observational study, we report on a large-scale system-wide Cleveland Clinic database (Ohio and Florida), to determine ICH risk in primary brain tumor patients who received DOACs and LMWH to guide safer anticoagulation choices for glioma patients.

Materials and Methods

Study Population

This observational cohort study was performed at Cleveland Clinic Foundation (CCF) facilities in Ohio and Florida. The study population was adult patients (≥18 years) with a diagnosis of glioma, and data was extracted by the CCF e-research team. International Classification of Diseases Tenth Revision (ICD-10) codes were used to identify patients with a diagnosis of glioma. The study (IRB #23-495) was deemed exempt from Institutional Review Board review due to use of pre-existing, de-identified data.

Inclusion criteria were: adult patients (≥18 years of age) with a diagnosis of glioma, receiving medical care at CCF (OH or FL) for at least two months between January 1, 2008, and January 1, 2023, and treated with heparin and/or a DOAC. The DOACs considered were apixaban, dabigatran, edoxaban, or rivaroxaban. Exclusion criteria were inferior vena cava (IVC) filter (due to altered VTE risk), anticoagulation duration less than 10 days, unfractionated (UF) heparin as the only anticoagulant, and patients who received both DOAC and LMWH (Figure 1). Anticoagulation for at least 10 consecutive days was required to exclude patients that only received transitional anticoagulation. UF heparin was excluded because of its distinct risk profile from LMWH. Patients who received both DOAC and LMWH during the study period were excluded to allow for statistical analysis of two independent groups. Extracted data were manually reviewed to determine each patient’s eligibility.

Figure 1.

Inclusion and exclusion criteria.

Variables

The primary outcome of interest was risk and severity of ICH. Patients with an ICH while prescribed anticoagulation were considered ICH events. ICH that occurred outside of the anticoagulation treatment period was not considered as an ICH event for statistical analysis. Similarly, post-operative ICH was noted separately because anticoagulation is routinely held prior to surgery. Computed Tomography (CT) imaging reports of patients with ICH events were manually reviewed by a board-certified neuro-oncologist (A.D.) blinded to anticoagulation status to classify ICH as either “trace/minor” (<10 cc), “subdural,” or “major/fatal” (>10 cc). For secondary analyses, patients were further divided based on tumor type: GBM, glioma not otherwise specified (NOS), high-grade glioma (WHO Grade 3 or 4 astrocytoma), low-grade glioma (WHO Grade 2 astrocytoma or oligodendroglioma), or oligodendroglioma NOS, as identified by ICD code.

A secondary outcome of interest was VTE rate within 6 months before or after primary brain tumor diagnosis, due to the possibility that these represented tumor-related events. Each patient was reviewed to document whether they were diagnosed with DVT and PE, only PE, or only DVT. Patients who had an unclear VTE diagnosis (“personal history of DVT,” “thrombophlebitis,” “embolism of unspecified site,” etc) were noted as “unclear VTE diagnosis” and not considered VTE events.

Statistical Analysis

Descriptive statistics were performed using the chi-squared test to compare categorical variables. Kaplan-Meier survival analysis was conducted to determine time-dependent risk of ICH. Time to event was defined as time from anticoagulation initiation to ICH diagnosis date. For patients without an ICH event (no ICH during study period, ICH outside of anticoagulation period, or post-operative ICH), date of death was used as the end point. If date of death was not applicable, then date of last recorded visit was used. All Kaplan-Meier analyses were truncated at 365 days to ensure adequate sample size to assess the ICH rate. Log-rank test was performed to compare ICH rate between study groups. P < .05 was considered statistically significant for all two-sided tests. All statistical analyses were performed using R Studio version 2023.

Results

Cohort Demographics

We identified 2558 adult patients with glioma seen at Cleveland Clinic (OH or FL) over at least a two-month interval between January 1, 2008, and January 1, 2023. Among these, 559 patients treated with a DOAC and/or heparin during the study period were included. We excluded 38 patients with an IVC filter, 116 patients whose only anticoagulation was UF heparin, 101 patients with anticoagulation duration less than 10 days, and 27 patients who received both LMWH and DOAC during the study period. After applying inclusion and exclusion criteria, 277 patients were retained for further analysis. Of these, 147 received a DOAC and 130 received LMWH (Figure 1). Within the DOAC group, 63.9% (94/147) received apixaban, 38.8% (57/147) received rivaroxaban, 2.7% (4/147) received dabigatran, and 0.7% (1/147) received edoxaban.

Demographic characteristics of the study cohort are shown in Table 3. The cohort included more males (59.6%) than females (40.4%), and most patients were White (90.6%). Approximately half (52.7%) of the study population had no history of smoking. There was no significant difference in sex (P = 1.0), race (P = .73), or smoking status (P = .51) between the DOAC and LMWH groups. Five (3.4%) patients in the DOAC cohort and four (3.1%) patients in the LMWH cohort had been prescribed bevacizumab during the study period (P = 1.0). One patient had an ICH after starting bevacizumab, but this event occurred prior to the start of rivaroxaban.

Table 3.

Descriptive characteristics of the DOAC versus LMWH cohort

Characteristics	P   a	DOAC						LMWH		Total
				Apixaban	Dabigatran	Edoxaban	Rivaroxaban
		n = 147		n = 94	n = 4	n = 1	n = 57	n = 130		n = 277
Sex	1
Male		88	59.9%	55	3	0	36	77	59.2%	165	59.6%
Female		59	40.1%	39	1	1	21	53	40.8%	112	40.4%
Race	.73
White		132	89.8%	84	4	1	52	119	91.5%	251	90.6%
Black		10	6.8%	6	0	0	4	6	4.6%	16	5.8%
Other		5	3.4%	4	0	0	1	5	3.8%	10	3.6%
Smoking status	.51
Every Day		8	5.4%	5	0	0	3	10	7.7%	18	6.5%
Former		45	30.6%	31	2	1	15	48	36.9%	93	33.6%
Never		82	55.8%	53	2	0	32	64	49.2%	146	52.7%
Other		12	8.2%	5	0	0	7	8	6.2%	20	7.2%
Tumor classification	.41
GBM		92	62.6%	56	3	1	36	94	72.3%	186	67.1%
Glioma NOS		30	20.4%	22	1	0	10	17	13.1%	47	17.0%
High-Grade Glioma		9	6.1%	7	0	0	2	9	6.9%	18	6.5%
Low-Grade Glioma		8	5.4%	3	0	0	5	5	3.8%	13	4.7%
Oligodendroglioma NOS		8	5.4%	6	0	0	4	5	3.8%	13	4.7%
Isocitrate dehydrogenase (IDH)	.12
Mutated		16	10.9%					6	4.6%	22	7.9%
Wild type		84	57.1%					74	56.9%	158	57.0%
Unknown		47	32.0%					50	38.5%	97	35.0%
Bevacizumab ever used	1
Yes		5	3.4%	2	1		2	4	3.1%	9	3.2%
No		142	96.6%					126	96.9%	268	96.8%
VTE within 180d of tumor dx?	.007
Yes		35	23.8%	17	1	1	20	53	40.8%	89	32.1%
DVT		21	14.3%	10	0	1	12	27	20.8%	49	17.7%
PE		10	6.8%	4	1	0	6	14	10.8%	25	9.0%
DVT + PE		4	2.7%	3	0	0	2	12	9.2%	15	5.4%
Unclear		5	3.4%	4	0	0	1	6	4.6%	11	4.0%
No		107	72.8%	73	3	0	36	71	54.6%	177	63.9%
ICH during study period?	.26
Yes		14	9.5%	10	0	0	5	19	14.6%	33	11.9%
During anticoagulation		3	2.0%	2 2.1%			1 1.8%	3	2.3%	6	2.2%
trace or minor				1			1	1
subdural				1			0	0
major or fatal				0			0	2
Post-operative				1			0	4
Before anticoagulation start				4			4	9
After anticoagulation end				3			0	3
No		133	90.5%	84	4	1	52	111	85.4%	244	88.1%

^aChi-Squared Test used to compare categorical variables for DOAC vs LMWH cohort.

Tumor classification, VTE frequency, and ICH frequency are described in Table 3. There were 186 (67.1%) patients with GBM, 47 (17.0%) with glioma NOS, 18 (6.5%) with high-grade glioma, 13 (4.7%) with low-grade glioma, and 13 (4.7%) with oligodendroglioma NOS. There was no significant difference in tumor grades between the DOAC and LMWH group (P = .41). Six (5%) patients in the LMWH cohort had IDH mutation, 74 (57%) were wild type, and 50 (38.5%) had unknown mutation status. Sixteen (11%) patients in the DOAC cohort had IDH mutation, 84 (57%) were wild type, and 47 (32%) had unknown mutation status (P = .12).

VTE was diagnosed at a median of 70 days following tumor diagnosis, and 89 (32.1%) patients had VTE within 6 months (before or after) of glioma diagnosis. Patients with VTE within 6 months of glioma diagnosis were significantly more likely to have been prescribed LMWH as compared with a DOAC (P = .007). Of these 89 patients, 49 (55%) had a DVT, 25 (28%) had a PE, and 15 (17%) had both DVT and PE. Also, of the 89 study patients with VTE within 6 months of diagnosis, 74% (66) had GBM and 1.1% (1) had low-grade glioma.

There were 33 (11.9%) patients that had an ICH event of any type (including before or after anticoagulation and post-operatively) during the study period (Figure 2). The total number of any ICH events during the study period did not significantly differ between the DOAC and LMWH groups (9.5% vs 14.6%, P = .26). Twenty-four ICH events were recorded within 6 months (before or after) of glioma diagnosis, of which 71% (17) occurred in patients with GBM, 8% (2) in high-grade glioma, 12.5% (3) in glioma NOS, 8% (2) in oligodendroglioma NOS, and none in patients with low-grade glioma.

Figure 2.

Kaplan-Meier curve representing risk of ICH for all study patients.

Primary Outcome: ICH during Anticoagulation Treatment

Six ICH events occurred while patients were receiving anticoagulation treatment. The median time from the start of anticoagulation to ICH for these six patients was 5.5 days (IQR: 2-23 days). No significant difference was observed in ICH events during anticoagulation between patients receiving DOAC versus LMWH (2.0% vs 2.3%, P = 1), apixaban versus LMWH (2.1% vs 2.3%, P = .26), or rivaroxaban versus LMWH (1.8% vs 2.3%, P = 1). Additionally, no significant difference was found in time-dependent risks of ICH between the DOAC and LMWH groups (P = 0.3, log rank test, Figure 3). Of the six ICH events during anticoagulation treatment, three (50%) were trace or minor, one (17%) was subdural, and two (33%) were major or fatal. Of the two major or fatal ICH, both occurred in patients receiving LMWH.

Figure 3.

Kaplan-Meier curves for risk of ICH in DOAC versus LMWH group demonstrating no significant difference in the time-dependent risk of ICH (P = .3).

Five (83%) of the ICH events occurred in patients with GBM, and one (17%) occurred in a patient with oligodendroglioma NOS. There was no statistically significant difference in ICH rate between patients when stratified by each tumor grade: GBM, glioma NOS, high-grade glioma, low-grade glioma, or oligodendroglioma NOS (P = .6, log-rank test, Supplementary Figure 1).

Discussion

Although glioma patients have an elevated risk of VTE compared to many other malignancies, there is also a relatively high (5%-8%) risk of intracranial hemorrhage, making anticoagulation decisions critical.^1,4,5,7 In this study, we found the risk of ICH of any type (including before or after anticoagulation and post-operatively) was slightly higher than previously reported, at 11.9%. LMWH and DOAC are the recommended anticoagulation options for brain tumor patients, but limited data exist regarding ICH risk as it pertains to diagnosis, anticoagulation use, and indication, particularly in low-grade gliomas. Our analysis demonstrates no significant difference in ICH risk between DOAC and LMWH, with the overall ICH risk during anticoagulation being relatively low (2.2%, n = 6).

In our cohort, 32% of patients had their first VTE within six months (before or after) of glioma diagnosis, which aligns with the reported 20%-30% risk of VTE in glioma patients.^1-3 The increased VTE risk in glioma is explained by several factors that are being actively explored: (1) coagulation factor expression, including tissue factor, factor VIII, and circulating D-dimer; (2) tumor-intrinsic factors, such as isocitrate dehydrogenase (IDH) mutation status, podoplanin expression, and GBM molecular subtype; (3) patient-related factors, such as leg paresis, age, body mass index (BMI), comorbidities (eg hypertension, asthma, prior coagulopathy), white blood cell (WBC) count, and previous VTE; and (4) treatment related factors, such as World Health Organization tumor grade, extent of tumor resection, surgery duration greater than 4 hours, corticosteroid administration, and chemotherapy agents.^5,30-33 As a result of missing mutation data in both cohorts, we could not account for IDH or MGMT status, which may be associated with risk of VTE.^6,32 However the rates of IDH mutation in patients with known mutation status were similar in both cohorts.

In addition, in both the LMWH and DOAC groups, more than half of patients did not have a VTE diagnosis within 6 months (before or after) tumor diagnosis. It is possible these patients had later or earlier VTE diagnosis, incorrectly documented VTE diagnosis, or other indications for anticoagulation, such as atrial fibrillation, total hip replacement, or prevention of VTE in thrombophilias. Our study compared anticoagulant safety regardless of indication, as the inherent risk of anticoagulation is present in any patient being treated. In a study of GBM patients with VTE, Reed-Guy and colleagues found no statistical difference in the incidence of clinically relevant ICH at 30 days between those receiving LMWH versus those receiving a DOAC. Our work extends this further than 30 days, includes lower grade gliomas, and is independent of anticoagulation indication.³⁴

In our study, the six ICH events occurred relatively early (median 5.5 days) after the start of anticoagulation, supporting a causal role. Furthermore, the rate of ICH was low, with only 2.0% of patients on DOAC and 2.3% of patients on LMWH having an ICH event while receiving anticoagulation. Our results are consistent with multiple prior studies that demonstrated no increased risk of ICH with DOAC compared to LMWH (Table 2).^25-28 Lee et al found no significant difference in ICH cumulative incidence even at an earlier 6 month mark.²⁸ Notably, in a study by Carney et al, the cumulative incidence of ICH was 36.8% in LMWH patients, which is considerably higher than our findings and other studies yet observed a 0% ICH risk in their DOAC group.25

ICH severity varies widely—from minor, asymptomatic hemorrhage discovered on imaging, to fatal events. However, the 2022 study by Reed-Guy and colleagues, found that at 6 months, clinically relevant ICH, defined as ICH that was fatal, symptomatic, required surgical intervention, and/or led to cessation of anticoagulation, was 0% in the DOAC group and 24% in the LMWH group (P = .001). There were four fatal ICH events in the LMWH group.³⁴ In contrast, Swartz and Drappatz saw a significantly greater rate of major bleeding in the DOAC group than the LMWH group (P = .03).²⁷ In our cohort, no major or fatal ICH events occurred with DOACs, while two occurred with LMWH. As such, while the existing studies generally establish non-­inferiority of DOACs compared to LMWH in terms of ICH risk, it is possible that DOACs are safer than LMWH. Indeed, in the systematic review and meta-analysis by Iyengar et al (N = 613 patients, 7 studies), of the studies evaluating patients with PBT, ICH risk was reduced with DOAC use, compared with LMWH (RR 0.35; 95% CI, 0.18-0.69; P = .003). The risk of fatal ICH was not different between DOAC and LMWH groups, however their study was not limited to gliomas.³⁵ Lastly, in our study, patients with underlying GBM had the highest rate of ICH events, consistent with the reported association between greater ICH risk and higher grade tumors.^1,5,7

Several limitations should be noted in the interpretation of our findings. First, we cannot rule out differences in unmeasured variables, such as age during anticoagulation treatment, treatment adherence, prior bleeding history, surgical history, radiation, use of other medications, etc The tumor classification was based on ICD code, which does not reflect advances in molecular glioma classification and is a key limitation with potential for advancement in future studies. The mean platelet count 6 months before the first VTE was 228 × 10³ (SD: 70 × 10³) in the DOAC group and 194 × 10³ (SD: 72 × 10³) in the LMWH group. However, these data were only available for 39% and 42% of the DOAC and LMWH groups, respectively; thus, unmeasured differences in platelet counts between groups contributing to differential ICH risk cannot be ruled out. Similarly, PT/INR data were missing for over 65% of both groups, so while a difference was not necessarily observed, the effects of missing data may confound this observation.

LMWH and DOAC dosing information was not available amongst study patients, though the dosing per institutional guidelines follows standard that of neurosurgical practice. There is no evidence to recommend any alternative to the standard of care dosing for VTE in this setting. Lastly, there is the possibility that patients included in this study could have had a recurrent VTE while receiving anticoagulation, but our analysis only compared first VTE diagnosis rates.

In clinical practice, there are additional patient-specific considerations that arise with the choice of anticoagulation. DOACs rely on absorption through the gastrointestinal tract and can be altered by anticancer treatment side effects, such as nausea, vomiting, and decreased appetite. Moreover, underweight elderly patients may have higher plasma levels of DOACs. Edoxaban and apixaban have recommended dose reductions based on low body weight.³⁶ DOACs are administered orally on a fixed dose regimen without need for routine blood monitoring but cannot be used in patients with end stage renal disease (ESRD).³⁷ Lastly, DOACs are P-glycoprotein substrates and apixaban and rivaroxaban rely on CYP3A4 metabolism, therefore there are many potential drug-drug interactions. DOACs have pharmacokinetic drug interactions with anti-seizure medications that induce cytochrome P450 or P-glycoprotein, leading to low DOAC concentrations and thus risk of treatment failure.³⁸ The incidence of seizures is 60%-85% in low grade glioma and 30%-50% in glioblastoma patients.³⁹

Key considerations with LMWH include variable metabolism and clearance among patients with impaired renal function, older age, and obesity. Inconvenience of administration has been found to be associated with lower patient adherence.²³ Among 2243 adult patients prescribed outpatient anticoagulation for cancer associated thrombosis, Guo et al found that 47% of patients prescribed LMWH and 12% of patients prescribed DOAC discontinued their therapy within 3 months for unspecified reasons.⁴⁰ This is supported by findings from Khorana et al. that rivaroxaban users were significantly more likely to remain on initial therapy compared to LMWH in cancer patients with VTE.⁴¹ A 2018 systematic review of VTE occurrence among cancer patients found better adherence with DOACs than with LMWH, potentially contributing to longer DOAC treatment duration and therefore greater recurrent VTE risk reduction.¹² Current literature, as well as this study, support that in patients with equal individual risk factors, DOACs may be the preferred choice for patients given the ease of administration and adherence.

In summary, this study suggests that DOACs are relatively safe in PBT patients, with a similar risk of ICH as compared to LMWH. Risk of ICH regardless of anticoagulation choice may be lower in low-grade glioma versus GBM, supporting the safety of anticoagulation in low-grade gliomas. Prospective studies are needed to definitively establish the anticoagulation risk in this population.

Supplementary Material

Supplementary material is available online at Neuro-Oncology Advances (https://academic.oup.com/noa).

Funding

There was no reportable funding for this study.

Conflict of Interest Statement

The authors have no conflicts of it erest to disclose.

Author Contributions

A.D., S.R.: Supervision, Conceptualization. R.S.A., A.D., S.S.B.: Investigation, Methodology, Data Acquisition, Data Analysis, Drafting. R.S.A., S.C., M.M.G., J.D.L., M.L., M.G.M., D.M.P., A.R.S., G.H.J.S., A.T.T., S.R., A.D.: Writing, Critical Review, Editing, Analysis Validation.

Ethics Approval

This project was reviewed by an appropriate institutional review board (IRB #23-495).

Data Availability

The original study data will be made available upon reasonable request.