Orally Administered Factor Xa Inhibitor, Rivaroxaban

Thromboembolic phenomena (TEP), such as deep venous thrombosis and pulmonary embolism, are a significant source of morbidity and mortality in neurosurgical patients (7,9,16,21,22,25,26). Neurosurgical patients are at increased risk of thromboembolism owing to surgery itself, prolonged immobility, and hypercoagulable states induced by intracranial pathology. Despite the regular use of prophylaxis, the occurrence of clinically evident TEP ranges from 2.3 to 19% (1,5,6,9,22). The optimal prophylactic regimen against TEP in neurosurgery has not yet been elucidated. Compression stockings have been shown to be beneficial (4,15,23), along with the use of low-molecular-weight heparin and minidose heparin (9,12,14,15,22). Several studies have also reported that subcutaneous heparin administered peri- and postoperatively is safe to use (3,9,15,22). Despite the demonstrated safety of prophylactic regimens and the high incidence of TEP in this patient population, approximately 60% of patients do not receive preventive measures (8) because of bleeding concerns. Thus, a more aggressive and universal protocol for TEP in neurosurgery patients, potentially with novel anticoagulants, seems to be indicated. An analogous situation exists in orthopedic surgery, in which anticoagulation for at least 10 days is the standard of care for total hip or knee arthroplasty (13), and extended prophylaxis for 5 weeks reduces the occurrence of venous thromboembolism more effectively than does short-term prophylaxis without increasing the risk of major bleeding (11). Recently, 3 articles described the results of thromboprophylaxis with an orally active, highly selective, direct inhibitor of Factor Xa, rivaroxaban, compared with the results of enoxaparin, a subcutaneously administered, indirect, nonselective Factor Xa inhibitor, in patients undergoing major orthopedic surgery (11,17,20). Collectively, more than 7000 patients were included in the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism studies (11,20). Patients randomly assigned to receive a fixed dose of 10 mg daily of rivaroxaban versus enoxaparin demonstrated similar results for total hip and total knee arthroplasty, respectively. Compared with enoxaparin, rivaroxaban was associated with significant reductions in symptomatic and asymptomatic venous thromboembolism and major venous thromboembolism, defined as a composite of proximal deep vein thrombosis, nonfatal pulmonary embolus, or death related to venous thromboembolism. The frequency of major complications, including bleeding, hemorrhagic wound complications, and hepatic enzyme elevations, was low and did not differ between the study groups. In addition, a third study of 2509 patients undergoing hip arthroplasty reported that extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism without resulting in a significant difference in complications, despite extended treatment in patients randomly assigned to the rivaroxaban group (17).FigureThe results of these studies have extensive implications in neurosurgical patients, as thromboprophylaxis is an integral element of treatment. The current options for extended thromboprophylaxis are limited. Warfarin requires frequent monitoring because of unpredictable hematological effects and numerous food and drug interactions (2). Furthermore, there is evidence to suggest that the incidence of major bleeding is greater than that with low-molecular-weight heparin preparations (24). Low-molecular-weight heparin preparations need to be administered subcutaneously, and their cost-effectiveness has been shown only if patients or caregivers can be taught to inject the medication at home (10). In contrast, rivaroxaban is an oral direct inhibitor of Factor Xa. The oral bioavailability of rivaroxaban is approximately 80%, and peak plasma concentrations are achieved in 2.5 to 4 hours, which makes TEP dosing easier to maintain (18,19). Moving forward, studies using oral pharmacological thromboembolic prophylaxis in neurosurgical patients will be critical. Although studies in orthopedic patients provide some promise for neurosurgical patients, it also remains unclear whether such aggressive deep vein thrombosis prophylaxis is cost-effective or warranted for patients who are expected to be ambulatory within 1 to 2 days after their procedures. RICARDO J. KOMOTAR, MD ROBERT M. STARKE, BA E. SANDER CONNOLLY, Jr., MD TECHNICAL & CLINICAL RESEARCH