The MAGELLAN Study: An Analysis of Outcomes Utilizing D-Dimer

Elevated D-dimer levels appear to be associated with an increased risk of venous thromboembolism (VTE) in acutely ill medical patients (Desjardins L et al. Arch Pathol Lab Med 2004;128:519–526; Fan J et al. Clin Invest Med 2011;34:E96–E104). In the multicenter, randomized, double-blind, double-dummy MAGELLAN study of rivaroxaban (35±4 days) versus enoxaparin (10±4 days) followed by placebo, rivaroxaban met both its primary efficacy endpoints (non-inferiority vs enoxaparin at Day 10 and superiority vs enoxaparin/placebo at Day 35) but was associated with a significant increase in clinically relevant bleeding.

To investigate whether elevated D-dimer levels were predictive of venous thromboembolic events in the MAGELLAN patient population and the effect of rivaroxaban in these patient groups.

D-dimer levels were determined at baseline, Day 10, and Day 35. Patients were divided into two groups: those with D-dimer levels of ≤2 × upper limit of normal (ULN) or >2 × ULN. The primary efficacy outcome (composite of asymptomatic proximal deep vein thrombosis and symptomatic VTE) and the principal safety outcome (clinically relevant bleeding, defined as major and non-major clinically relevant bleeding) were assessed at Day 10 and Day 35. The prespecified net clinical benefit (NCB) was defined as the composite of these two endpoints. A post hoc multivariate analysis was performed to control for covariates including D-dimer.

Baseline median D-dimer level was 0.94 μg/mL in all patients, and was higher in those patients with a primary efficacy outcome event (1.98 μg/mL) compared with those without such an event (0.92 μg/mL). Patients with baseline D-dimer >2 × ULN were at approximately fourfold greater risk of a venous thromboembolic event at Day 10 compared with those patients with a baseline D-dimer ≤2 × ULN (Table). Rivaroxaban remained non-inferior for the primary efficacy outcome compared with enoxaparin at Day 10 in the D-dimer >2 × ULN group. At Day 35, in patients with baseline D-dimer >2 × ULN, rivaroxaban reduced the relative risk of the primary efficacy outcome by 29% (2.8% absolute risk reduction; p=0.01) compared with enoxaparin/placebo (Table). In patients with a baseline D-dimer ≤2 × ULN there was no significant difference between the enoxaparin and rivaroxaban groups. Patients with a high D-dimer level at baseline were at increased risk of an event occurring between Day 11 and Day 35, and rivaroxaban beneficially impacted outcome compared with placebo during this period (Table). In both the D-dimer groups clinically relevant bleeding remained significantly higher in the rivaroxaban compared with the enoxaparin/placebo group across the study period. In the NCB analysis, patients with baseline D-dimer >2 × ULN vs ≤2 × ULN had hazard ratios of 0.96 versus 1.63, respectively (Day 10), and 1.03 versus 1.71, respectively (Day 35). The multivariate analysis demonstrated that D-dimer concentration was a strong and significant predictor of the risk of VTE (point estimate for D-dimer >2 × ULN vs ≤2 × ULN 2.286; p<0.0001), which resulted in an improved NCB.

This analysis suggests that the use of a baseline D-dimer assay can identify a group of acutely ill patients at high and continued risk of VTE, in whom the use of extended thromboprophylaxis with rivaroxaban provides both an efficacy benefit and an overall acceptable NCB.

Cohen:Astellas: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mitsubishi Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Schering Plough: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer: Employment. Burton:Johnson & Johnson: Employment. Büller:Bayer HealthCare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haskell:Johnson & Johnson: Employment, Equity Ownership. Hu:Bayer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astra Zeneca: Consultancy. Hull:Sanofi-Aventis: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Mebazaa:Bayer: Consultancy. Merli:sanofi-aventis: Research Funding; BMS: Research Funding; Bayer: Research Funding. Schellong:Sanofi Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer HealthCare: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Leo Pharma: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Canyon Pharmaceuticals: Consultancy, Honoraria; UCB Pharma: Honoraria; MEDAC: Consultancy, Honoraria. Spyropoulos:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; sanofi-aventis: Consultancy; eisai: Consultancy; DSMB Astellas: Consultancy; BMS: Consultancy. Tapson:sanofi-aventis: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding.