Thromb Haemost 2019; 119(11): 1886-1887
DOI: 10.1055/s-0039-1695769
Letter to the Editor
Georg Thieme Verlag KG Stuttgart · New York

Safety of Primary Thromboprophylaxis Using Apixaban in Ambulatory Cancer Patients with Intracranial Metastatic Disease or Primary Brain Tumors

Sébastien Miranda
1  Department of Internal Medicine, Vascular and Thrombosis Unit, Rouen University Hospital, Normandie University, UNIROUEN, INSERM U1096, Rouen, France
,
Ygal Benhamou
1  Department of Internal Medicine, Vascular and Thrombosis Unit, Rouen University Hospital, Normandie University, UNIROUEN, INSERM U1096, Rouen, France
,
2  Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Marc Carrier
2  Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
› Author Affiliations
Further Information

Publication History

21 May 2019

04 July 2019

Publication Date:
10 October 2019 (online)

Venous thromboembolism (VTE) is a frequent complication among cancer patients with an estimated incidence of between 12.6 and 68 per 1,000 patient-years in high-risk subgroups.[1] Patients with primary brain tumors are particularly at high risk with an overall incidence of 48 per 1,000 patient-years.[2] The risk of VTE in the setting of brain metastasis is unknown, but overall, metastases increase the risk of VTE in cancer patients. A population-based study reported that the adjusted relative risks of VTE were 17.1 (95% confidence intervals [CIs]: 12.6–23.3) and 2.9 (95% CI: 1.5–5.5) in patients with stage IV and I disease, respectively.[3] Therefore, clinicians might be compelled to consider thromboprophylaxis in cancer patients with intracranial metastatic disease or primary brain tumors. However, clinicians might also be reluctant to use thromboprophylaxis in these patients due to a perceived higher risk of intracranial bleeding. A prior study assessing thromboprophylaxis with low-molecular-weight heparin (LMWH) in patients with newly diagnosed malignant gliomas suggested that thromboprophylaxis decreased VTE complications (hazard ratio [HR]: 0.51; 95% CI: 0.19–1.4), it also seemed to be associated with increased intracranial bleeding (HR: 4.2; 95% CI: 0.48–36).[4] The risks of major and intracranial bleeding complications with thromboprophylaxis using a direct oral anticoagulation (DOAC) are unknown for this patient population. We sought to address this important knowledge gap by evaluating the risks and benefits of using apixaban (2.5 mg twice daily) for the prevention of VTE in ambulatory cancer patients with intracranial metastatic disease or primary brain tumors.

We performed a post hoc analysis of the AVERT trial.[5] Overall, 574 ambulatory cancer patients at intermediate-to-high risk of VTE were randomized to receive apixaban 2.5 mg twice daily or placebo for up to 6 months. Of the 574 patients who underwent randomization, 275 and 288 were included in the placebo and apixaban groups, respectively. The primary efficacy outcome was the first episode of objectively documented VTE (proximal deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) within the first 180 days (±3 days) from randomization. The main safety outcomes included major bleeding defined by the International Society of Thrombosis and Haemostasis and clinically relevant nonmajor bleeding.[6] Overall, 24 (4.2%) patients had a primary brain tumor (glioblastoma, astrocytoma high grade) and 12 (2.1%) had intracranial metastatic disease. Among these, 21 and 15 patients received apixaban or placebo, respectively. Baseline characteristics are depicted in [Table 1]. There was no difference between the groups according to age, gender, primary tumor types, and antiplatelet use. Twelve patients discontinued the study intervention earlier than 6 months (9 and 3 patients receiving apixaban and placebo, respectively). None of these patients discontinued the intervention because of a bleeding complication. Overall, there were no intracranial or major bleeding complications among these patients ([Table 1]). One patient (4.8%; 95% CI: 0.9–22.7%) had a clinically relevant nonmajor bleeding related to epistaxis. One patient (4.8%; 95% CI: 0.9–22.7%) with primary central nervous system lymphoma receiving apixaban had a PE. Three patients (20%; 95% CI: 7.0–45.2%) with primary brain tumors receiving placebo had VTE complications (lower limb proximal DVT [n = 2], PE [n = 1]) ([Table 1]).

Table 1

Baseline characteristics and outcome measures

Apixaban

(N = 21)

Control

(N = 15)

Males, n (%)

11 (52.4)

8 (53.3)

Mean age, y ± SD

56.3 ± 11.7

59.6 ± 9.4

Mean weight, kg ± SD

86.1 ± 20.7

81.3 ± 16.5

Creatinine clearance ≤ 50 mL/min, n (%)

0

0

Previous history of VTE

1 (4.8)

1 (6.7)

Tumor type, n (%)

 Brain

14 (38.9)

10 (27.8)

 Lung

4 (19)

3 (8.3)

 Breast

2 (9.5)

1 (2.8)

 Lymphoma

1 (2.8)

0

 Aspirin use, n (%)

4 (19)

2 (13.3)

 Early discontinuation

9 (42.9)

3 (20)

 Mean time on treatment (d ± SD)

137.5 ± 60.7

166 ± 35.6

Outcomes

 Major bleeding

0

0

 CRNMB, n (%; 95% CI)

1

(4.8; 0.9–22.7)

0

 VTE, n (%; 95% CI)

1

(4.8; 0.9–22.7)

3

(20; 7.0–45.2)

Abbreviations: CI, confidence intervals; CRNMB, clinically relevant nonmajor bleeding; SD, standard deviation; VTE, venous thromboembolism.


The results are reassuring and potentially suggest that thromboprophylaxis with apixaban might be safe in patients with intracranial metastatic disease or primary brain tumors. Our results are consistent with other recently published literature. A cohort study evaluated the safety of DOACs at therapeutic dosing for the management of VTE patients with intracranial metastatic disease or primary brain tumors.[7] The study included 67 patients with primary brain tumors (DOACs [n = 20]; LMWH [n = 47]) and 105 patients with intracranial metastatic disease (DOACs [n = 21]; LMWH [n = 84]). No patients with a primary brain tumor receiving DOACs had intracranial hemorrhage (ICH), and DOACs did not increase the risk of ICH relative to LMWH in patients with intracranial brain metastases.[7] Therefore, the use of apixaban at prophylactic doses is likely safe to administer for primary prevention in this patient population. However, our findings should be taken with caution. An important limitation is the relatively small sample size leading to potential imprecision and broad CIs. Furthermore, the impact of known bleeding risk factors (e.g., renal dysfunction, anemia, etc.) could not be accounted for given the small number of events. Finally, in our trial there were no patients with vascularized tumors (e.g., melanoma, kidney, etc.), and therefore, the results may not be applicable to these patients.[8]

Apixaban 2.5 mg twice daily seems safe among ambulatory cancer patients with intracranial metastatic disease or primary brain tumors. Primary prevention in this very high-risk population seems to prevent VTE complications and thereby avoids eventual use of therapeutic doses of anticoagulants in a population patient considered high risk for bleeding.