Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN Study

Abstract

Acutely ill medical patients are at risk of venous thromboembolism (VTE) and VTE-related mortality during hospitalization and posthospital discharge, but widespread adoption of extended thromboprophylaxis has not occurred. We analyzed a subpopulation within the MAGELLAN study of extended thromboprophylaxis with rivaroxaban to reevaluate the benefit risk profile. We identified 5 risk factors for major and fatal bleeding after a clinical analysis of the MAGELLAN study and analyzed efficacy and safety with these patients excluded (n = 1551). Risk factors included: active cancer, dual antiplatelet therapy at baseline, bronchiectasis/pulmonary cavitation, gastroduodenal ulcer, or bleeding within 3 months before randomization. We evaluated efficacy, safety, and benefit risk using clinically comparable endpoints in the subpopulation. At day 10, rivaroxaban was noninferior to enoxaparin (relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.58-1.15) and at day 35 rivaroxaban was significantly better than enoxaparin/placebo (RR = 0.68, 95% CI = 0.53-0.88) in reducing VTE and VTE-related death. Major bleeding was reduced at day 10 (RR = 2.18, 95% CI = 1.07-4.44 vs 1.19, 95% CI = 0.54-2.65) and at day 35 (2.87, 95% CI = 1.60-5.15 vs 1.48, 95% CI = 0.77-2.84) for MAGELLAN versus this subpopulation, respectively. The benefit risk profile was favorable in this subpopulation treated for 35 days, with the number needed to treat ranging from 55 to 481 and number needed to harm from 455 to 1067 for all pairwise evaluations. Five exclusionary criteria defined a subpopulation of acutely ill medical patients with a positive benefit risk profile for in-hospital and extended thromboprophylaxis with rivaroxaban.

Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis

“…The MAGELLAN subpopulation, 4 which was not prespecified as a part of the original trial methodology, consisted of patients in the MAGELLAN trial without any of the following five risk factors for International Society on Thrombosis and Haemostasis (ISTH) defined major bleeding: active cancer at randomization, dual antiplatelet therapy at baseline, a medical history of bronchiectasis/pulmonary cavitation, active gastroduodenal ulcer, or any bleeding in the previous 3 months prior to randomization. Patients who met one or more of these criteria prior to or at randomization were excluded from the MAGELLAN subpopulation used in this analysis.…”

“…1,2 Data from randomized controlled trials of ET with the direct oral anticoagulants (DOACs) betrixaban and rivaroxaban reveal net clinical benefit of such a strategy in key patient groups or subgroups, and these agents have gained regulatory approval in the US. 3,4 However, identification of such patients using a standardized approach remains difficult.…”

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up

“…After hospital discharge from acute medical illness, extended prophylaxis with LMWH (70) or direct oral anticoagulants (DOACs) (71-74) can reduce the risk of VTE, at the cost of increase in bleeding events, including major bleeding (75,76). While no data specific to COVID-19 exist, it is reasonable to employ individualized risk stratification for thrombotic and hemorrhagic risk, followed by consideration of extended prophylaxis (for up to 45 days) for patients with elevated risk of VTE (e.g., reduced mobility, co-morbidities such as active cancer, and [according to some authors in the writing group], elevated D-dimer >2 times the upper normal limit) who have low risk of bleeding (74,77,78).…”

Pharmacotherapy for Prevention and Management of Thrombosis in COVID-19

“…4 Based on studies prior to the COVID-19 era, rivaroxaban and betrixaban would be reasonable agents for this purpose. 15,16 LMWHs are also an alternative for this indication.…”