Early discontinuation has been announced for the Phase III NAVIGATE ESUS study – led by Bayer AG and its development partner Janssen Research & Development, LLC – which had been evaluating the safety and efficacy of the novel oral anticoagulant rivaroxaban (Xarelto®) versus aspirin in secondary prevention of stroke and systemic embolism in patients with recent embolic stroke of undetermined source (ESUS). Such patients have documented embolic stroke upon neuroimaging, but without identified cause, e.g. atherosclerotic disease or atrial fibrillation.1
The trial enrolled 7,214 patients across 459 sites in 31 countries, randomising to 15 mg rivaroxaban – a non-vitamin K antagonist – or 100 mg aspirin, taken once daily. The primary efficacy endpoint was stroke (ischaemic, haemorrhagic and undefined stroke, transient ischaemic attack with positive neuroimaging) and systemic embolism, with the primary safety endpoint set at major bleeding.
The study’s Independent Data Monitoring Committee (IDMC) recommended cessation of the trial after comparable efficacy was seen between aspirin and rivaroxaban, with the latter deemed as having “very little chance” of showing superiority if the study was continued. Furthermore, while bleeding rates were low in both groups, increased bleeding when compared to aspirin was seen in the rivaroxaban arm.
“Patients with ESUS currently have limited treatment options and the role of anticoagulants in this area remains uncertain,” said Joerg Moeller, Member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. “We will now analyse the data from NAVIGATE ESUS to better understand this outcome and its implications.”
Rivaroxaban was previously tested in the landmark ROCKET AF trial,2 demonstrating non-inferiority to warfarin for prevention of stroke or systemic embolism in the treatment of nonvalvular atrial fibrillation. No significant difference in major bleeding was seen between treatment groups, but intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.
Following the ROCKET AF trial, rivaroxaban has been met with approval for several indications, including the treatment/prevention of pulmonary embolism (PE) and deep vein thrombosis (DVT), prevention of venous thromboembolism in elective knee or hip surgery, and prevention of atherothrombotic events after an acute coronary syndrome in adult patients with elevated cardiac biomarkers and no prior stroke or transient ischaemic attack (TIA) when co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine.
A complete data analysis from the Phase III NAVIGATE ESUS study is expected to be presented in 2018.
1. Bayer AG. ‘Bayer’s NAVIGATE ESUS study halted early as it indicated comparable efficacy between treatment arms’, Bayer AG, October 5, 2017, http://press.bayer.com/baynews/baynews.nsf/id/Bayers-NAVIGATE-ESUS-study-halted-early-as-it-indicated-comparable-efficacy-between-treatment-arms (accessed 18 October, 2017).
2. Patel, M.R. et al. ‘Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation’, New England Journal of Medicine, vol. 365, no. 10, 2011, p. 883.