Efficacy and Safety of Rivaroxaban in the Prevention of Venous Thromboembolism in Glioma Patients

Venous thromboembolism (VTE) is a disorder in which blood clots abnormally in the veins, resulting in complete or incomplete blockage of blood vessels, including deep vein thrombosis and pulmonary embolism of the lower extremities, and is a common complication in patients with malignancy. In a retrospective analysis of the causes of death in patients with active cancer receiving chemotherapy, thromboembolic disease was the second leading cause of death, with VTE accounting for the vast majority. The risk of venous thromboembolism varies depending on the type of cancer, but it has been reported that the incidence of brain tumors can be greater than 20 percent per year, especially in the early postoperative period. High-grade gliomas are common brain tumors with a 20 to 30 percent risk of venous thrombosis during treatment, and postoperative lower extremity dysfunction in patients with high-grade gliomas is considered a high-risk factor for venous thrombosis. Because many high-grade gliomas are located in or adjacent to functional areas, such as frontopariparietal glioma, parietal glioma, thalamic glioma, and others, patients are more likely to develop limb dysfunction. Therefore, it is necessary to prevent venous thromboembolism for patients with high-grade glioma with lower extremity dysfunction after surgery.

Risk factors for venous thromboembolism can be divided into patient-related, tumor-related, and treatment-related. Patient-related factors include age >65 years, weight gain, hypertension, A or AB blood type, previous history of venous thrombosis or pulmonary embolism, and paraparesis. Risk factors associated with tumors include high-grade glioma, tumor diameter >5 cm, and residual tumor after surgery. Treatment-related risk factors include early postoperative period (within 30 days), surgery time >4 hours, chemotherapy, anti-vascular endothelial growth factor therapy, hormonal therapy, and central venous catheterization. Lower extremity dysfunction in patients with glioma is both tumor-related and treatment-related. In the past, clinicians did not routinely administer prophylactic anticoagulation to glioma patients with lower limb disorders because the use of anticoagulants would increase the chance of postoperative intracranial hemorrhage. However, it was reported that the risk of venous thromboembolism in patients with lower extremity dysfunction was 2.6 to 3.6 times than in those without lower extremity dysfunction, and recent studies have shown that the combination of perioperative compression stockings, pneumatic plantar venous pumps and low molecular weight heparin (LMWH) maximizes the prevention of venous thromboembolism in critically neurosurgical patients without a high risk of bleeding. Moreover, a previous randomized, double-blind prospective clinical trial evaluated the safety of heparin in the perioperative period of brain tumors, and the results suggested that the perioperative use of low-dose heparin in brain tumors was safe and effective, and did not increase the risk of bleeding compared with controls. Another meta-analysis further confirmed the safety of LMWH or unfractionated heparin for the prevention of venous thromboembolism after neurosurgery.

However, there are few studies on the use of LMWH in this population, and there is no consensus on the safety of LMWH for the prevention of venous thromboembolism in this population. A phase III randomized controlled trial in patients with high-grade glioma, initiated in 2002, evaluated the safety and efficacy of postoperative LMWH for the prevention of venous thromboembolism, suggesting that LMWH can reduce the occurrence of venous thrombosis but also increase the risk of bleeding. The Eastern Cooperative Oncology Group has also evaluated the use of LMWH for the prevention of glioblastoma, and the use of LMWH reduced thrombosis without increasing the probability of intracranial hemorrhage. In addition, the scale and number of cases in the above studies were small. Therefore, there is an urgent need to explore an effective and safe method to prevent postoperative venous thromboembolism in glioma patients with lower limb dysfunction.

Rivaroxaban is an oral anticoagulant that directly inhibits Xa and thrombin and is widely used in noncancer-associated VTE due to its oral availability, high bioavailability with no need for frequent coagulation monitoring. In the study of tumor-related VTE, rivaroxaban has preliminarily shown no less effect than LMWH in the prevention and treatment of venous thromboembolism. Mohamed et al. systematically reviewed and meta-analyzed the efficacy and complications of LMWH and rivaroxaban in cancer-related thrombosis, and the results suggested that rivaroxaban had a lower risk of VTE recurrence and all-cause mortality, and that the main bleeding risk was no different from that of LMWH. In a phase III SELECT-D pilot study comparing the efficacy and complications of cancer-related thrombosis with the two agents, rivaroxaban was associated with a low risk of VTE recurrence and a low risk of major and non-major bleeding. Therefore, rivaroxaban has a good role in the prevention of tumor-related VTE. And because of its convenience of being oral and not requiring frequent monitoring, it is of great significance for clinical treatment.

In summary, in view of the current lack of research on postoperative prophylactic anticoagulation therapy in patients with glioma, our center plans to lead a multi-center, randomized, double-blind controlled prospective clinical trial in glioma patients with lower limb dysfunction after surgery. To determine whether the addition of rivaroxaban has a more active preventive effect on postoperative venous thromboembolism, and to explore the safety of rivaroxaban in preventing postoperative venous thromboembolism in glioma patients lower limb dysfunction.