Rivaroxaban and Extended Thromboprophylaxis in Acutely Ill Medical Patients with History of Cancer: Insights from the Magellan and Mariner Studies
Authors: Spyropoulos Alex C. , Lipardi Concetta , Cohen Alexander T , Vučković Biljana , Xu Jianfeng , Lu Wentao , Spiro Theodore E. , Barnathan Elliot S. , Raskob Gary E. 
Published: November 2019

Background: Acutely ill medical patients with a history of cancer are at risk of venous thromboembolic events (VTE) in hospital and after discharge. Rivaroxaban was evaluated for VTE prevention in acutely ill medical patients in two randomized clinical trials of extended thromboprophylaxis with rivaroxaban. MAGELLAN (NCT00571649) included patients with active cancer undergoing treatment as well as those with only a history of cancer while the MARINER study (NCT02111564) only included patients with a history of cancer but not active cancer. In MAGELLAN treatment began in hospital (rivaroxaban 10mg QD for 35±4 days vs enoxaparin for 10±4 days followed by placebo), whereas in MARINER, treatment began at discharge (rivaroxaban 10mg QD or 7.5mg QD for those with baseline creatinine clearance 30-&lt;50ml/min vs placebo) for 45 days. In this post hoc subgroup analysis, we compared rivaroxaban versus enoxaparin/placebo (MAGELLAN) or placebo (MARINER) for primary efficacy and key safety outcomes in acutely ill medical patients with only a history of cancer compared to those with no history of cancer.
Methods: MAGELLAN and MARINER patients with a history of cancer or cancer in remission but without active cancer undergoing treatment were identified and compared to the subgroup of patients with no history of cancer. Relevant baseline demographics and cancer characteristics were summarized. The primary efficacy outcome was the composite of asymptomatic proximal deep vein thrombosis (DVT), symptomatic VTE and VTE-related death at Day 35 in the modified intention to treat population in MAGELLAN and the composite of symptomatic VTE and VTE-related death up to Day 45 in the intention to treat population in MARINER. The key safety outcome analyzed for both studies was the incidence of clinically relevant bleeding (the composite of ISTH major or non-major clinically relevant bleeding) on treatment + 2 days in randomized subjects who took at least one dose of study drug.
Results: In MAGELLAN in the subgroup with a history of cancer, the most frequent reason for hospitalization was an acute infectious disease (61%). In the history of cancer subgroup, the primary efficacy outcome occurred in 8/203 (3.9%) patients on rivaroxaban and in 16/192 (8.3%) patients on enoxaparin/placebo (RR=0.45; 95%CI 0.19, 1.03) whereas in the subgroup with no cancer, it occurred in 95/2467 (3.85%) in patients on rivaroxaban and in 133/2562 (5.19%) in those on enoxaparin/placebo (RR=0.74; 95%CI 0.57, 0.96). Clinically relevant bleeding was increased with rivaroxaban to a similar degree in both subgroups in MAGELLAN. There was no fatal bleeding in patients with history of cancer (Table). In MARINER in the subgroup with a history of cancer, the most frequent reason for hospitalization was heart failure (36%). In the history of cancer subgroup, the primary efficacy outcome occurred in 5/488 (1.02%) in patients in the rivaroxaban group and in 7/533 (1.31%) in patients in the placebo group (HR=0.76; 95%CI 0.24, 2.40) while in those without cancer, it occurred in 45/5519 (0.82%) patients in the rivaroxaban group and in 59/5479 (1.08%) in the placebo group (HR=0.76; 95%CI 0.51,1.11). Clinically relevant bleeding was increased with rivaroxaban to a similar degree in both subgroups in MARINER. There was no fatal bleeding in patients with history of cancer (Table). In both studies, major bleeding was similar in both treatment groups in the subgroup with a history of cancer.
Conclusion: VTE was generally more frequent in patients with a history of cancer than those without it. In MAGELLAN, rivaroxaban appears more effective compared with enoxaparin/placebo in reducing the primary composite efficacy outcome in the subgroup with a history of cancer than those without cancer, whereas in MARINER, the reduction in symptomatic VTE and VTE-related death with rivaroxaban was similar in both subgroups. Although clinically relevant bleeding was increased in both studies, major bleeding was similar in those with a history of cancer in both studies and no fatal bleeding events were observed in the history of cancer subgroup in either study. Altogether, these data suggest a generally favorable benefit risk profile for extended thromboprophylaxis with rivaroxaban in acutely ill medical patients with a history of cancer.

Disclosures
Spyropoulos: Janssen R&D, LLC: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Bayer Healthcare: Consultancy; Portola: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Cohen:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Takeda: Consultancy; GLG: Consultancy; Leo Pharma: Consultancy; Boston Scientific: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Navigant: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; McKinsey: Consultancy; Medscape: Consultancy, Speakers Bureau; Temasek Capital: Consultancy; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; Guidepoint Global: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau. Vučković:Janssen Research & Development, LLC: Consultancy. Xu:Janssen R&D, LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. Raskob:Tetherex: Consultancy; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Eli Lilly: Consultancy; Novartis: Consultancy; Janssen R&D, LLC: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

OffLabel Disclosure:
Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.