Rivaroxaban Compared with Enoxaparin for the Prevention of Venous Thromboembolism In Acutely Ill Medical Patients: MAGELLAN Study Methodology

The results of clinical trials comparing low molecular weight heparins or a pentasaccharide with placebo controls have provided compelling evidence for the benefits of pharmacologic thromboprophylaxis for 10–14 days in acutely ill medical patients (Samama et al. N Engl J Med 1999;341:793–800; Leizorovicz et al. Circulation 2004;110:874–879; Cohen et al. BMJ 2006;332:325–329). Oral rivaroxaban 10 mg once daily (od) has been shown to be effective and well tolerated for the prevention of venous thromboembolism (VTE) for 31–39 days after elective hip replacement (Eriksson et al. N Engl J Med 2008;358:2765–2775; Kakkar et al. Lancet 2008;372:31–39) and for 10–14 days after knee replacement surgery in adult patients (Lassen et al. N Engl J Med 2008;358:2776–2786; Turpie et al. Lancet 2009;373:1673–1680).

To compare the efficacy and safety of thromboprophylaxis with oral rivaroxaban 10 mg od for (1) up to 14 days and (2) up to 39 days with subcutaneous enoxaparin 40 mg od for up to 14 days in patients with acute medical illness requiring hospitalization.

MAGELLAN (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized acutely iLL medical patients comparing rivaroxabAN with enoxaparin) was a multinational, multicenter, randomized, double-blind, double-dummy, active comparator controlled study in patients with current reduced mobility that was likely to persist. All enrolled patients received study medication on day 1 (defined as the day of randomization), underwent mandatory bilateral lower limb venous ultrasonography on day 10±4 and on day 35±4, and were followed until day 90±7. Suspected symptomatic VTE was investigated promptly using appropriate vascular and pulmonary imaging procedures. The inclusion criteria were: age ≥40 years; immobilization; heart failure, active cancer, acute ischemic stroke, acute infection, acute inflammatory or rheumatic disorders, or acute respiratory insufficiency. Patients with acute ischemic stroke without leg paresis or paralysis, acute infection, acute inflammatory or rheumatic disorders, or acute respiratory insufficiency required at least 1 additional risk factor for VTE, e.g. age ≥75 years, previous VTE, previous cancer or heart failure, severe venous disease, thrombophilia, recent major surgery or serious trauma, hormone replacement therapy or morbid obesity (body mass index ≥35 kg/m²). The exclusion criteria included an increased risk of bleeding; prohibited drugs or procedures, e.g. anticoagulant therapy; and concomitant conditions or diseases, e.g. allergies, severe renal or liver disease. The primary efficacy outcome was the composite of asymptomatic proximal deep vein thrombosis (DVT) detected by mandatory venous ultrasonography, symptomatic proximal and distal DVT, symptomatic pulmonary embolism, and fatal VTE reported during the treatment phase of the study. There were 2 efficacy analysis populations, pertaining to the 2 primary efficacy endpoints. The study was powered at the 90% level to show non-inferiority at day 10±4 and superiority at day 35±4. The primary safety outcome was the composite of major bleeding events and clinically relevant non-major bleeding events. Sparse pharmacokinetic/pharmacodynamic sampling was performed by measuring rivaroxaban levels at peak and trough time points in all patients. In selected centers, a full pharmacokinetic/pharmacodynamic profile was performed. Pharmacogenetic and health economic outcomes were also assessed.

The first patient was enrolled in December 2007. As of July 2010, 8,101 subjects have been enrolled in the study from 556 centers in 52 countries. The mean age of patients is approximately 69 years, and around 46% are female. Approximate distributions of the acute medical conditions are as follows: 34% have heart failure, 32% have acute infectious diseases, 24% have acute respiratory insufficiency, 17% have acute ischemic stroke, 8% have active cancer, and 5% have acute inflammatory and rheumatic diseases.

MAGELLAN will determine the efficacy and safety of oral rivaroxaban (short- and extended-duration regimens) compared with the current standard of care in a diverse population of acutely ill medical patients with reduced mobility and other risk factors for venous thromboembolic disease.

Cohen:Bayer Schering Pharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding. Spiro:Bayer Healthcare Pharmaceuticals Inc.: Employment. Büller:Bayer Schering Pharma: Consultancy, Research Funding. Haskell:Johnson & Johnson Pharmaceutical Research & Development L.L.C.: Employment. Hu:Bayer Schering Pharma: Research Funding. Hull:Bayer Schering Pharma: Research Funding. Mebazaa:Bayer Schering Pharma: Research Funding. Merli:Bayer Schering Pharma: Research Funding. Schellong:Bayer Schering Pharma: Research Funding. Spyropoulos:Bayer Schering Pharma: Research Funding. Tapson:Bayer Schering Pharma: Research Funding.