Results from the global phase 3b ENSURE-AF study of 2,199 patients with non-valvular atrial fibrillation (NVAF) undergoing electrical cardioversion were presented recently at the ESC Congress 2016 in Rome, and published online in The Lancet. The study demonstrated that oral, once-daily edoxaban (Lixiana) met the study’s primary endpoints, demonstrating comparable efficacy and safety to well-managed enoxaparin/warfarin (mean time in therapeutic range on warfarin was 70.8%) for the prevention of stroke and other blood clot complications.
ENSURE-AF is a PROBE parallel group study designed to evaluate the efficacy and safety of once-daily edoxaban versus enoxaparin/well-managed warfarin in patients with NVAF undergoing electrical cardioversion. For the primary efficacy outcome evaluating the composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, edoxaban demonstrated a similar incidence compared to enoxaparin/warfarin (0.5% vs. 1.0%, respectively) (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.12 to 1.43). The main difference between the treatment groups was driven by cardiovascular mortality, with one event in the edoxaban group and five events in the enoxaparin/warfarin group (0.1% vs. 0.5%, respectively).
“The results of ENSURE-AF show that once-daily edoxaban may be a viable treatment option for NVAF patients undergoing cardioversion, as demonstrated by the largest prospective dataset for a non-vitamin K antagonist oral anticoagulant in this clinical setting to date,” said Andreas Goette, MD, Chief Physician, St. Vincenz-Hospital Paderborn, Germany, Department of Cardiology and Intensive Care Medicine and principal study investigator. “These results may have important clinical implications for newly diagnosed non-anticoagulated AF patients undergoing cardioversion. According to the study protocol, a newly diagnosed non-anticoagulated AF patient was started on edoxaban, and the cardioversion procedure was scheduled as early as two hours following the start of treatment when applying a TEE-guided approach.”
For the combined principal safety outcome of the incidence of major and clinically-relevant non-major (CRNM) bleeding, events occurred in 1.5% of patients in the edoxaban group and 1.0% in the enoxaparin/warfarin group (OR, 1.48; 95% CI, 0.64 to 3.55). The difference was statistically non-significant. The incidence of major bleeding was numerically lower in the edoxaban group compared to the enoxaparin/warfarin group (0.3% vs. 0.5%, respectively) (OR: 0.61; 95% CI, 0.09 to 3.13). No intracranial bleedings were reported in the study in either of the treatment groups. No fatal bleeding was reported in the edoxaban group vs. one patient in the enoxaparin/warfarin group.
The result for the net clinical outcome (composite of stroke, systemic embolic event, myocardial infarction, cardiovascular mortality, and major bleeding) was 0.7% in the edoxaban group and 1.4% in the enoxaparin/warfarin group (OR=0.50; 95% CI, 0.19 to 1.25) during the overall study period.
The trial was not adequately powered to demonstrate statistical differences for efficacy or safety endpoints, but provides further insights on the use of edoxaban in the setting of electrical cardioversion of NVAF.
In the study, patients were stratified according to cardioversion approach (TEE or non-TEE), a patient’s prior experience taking anticoagulants at the time of randomisation (ie. anticoagulant-experienced or naïve), and edoxaban dose (60mg once-daily or reduced 30mg once-daily). Patients were randomised in a 1:1 ratio to two treatment groups within each stratum. Edoxaban was dosed at 60mg once-daily. The dose was reduced to edoxaban 30mg once-daily for those patients if one or more factors (renal impairment, low body weight, or concomitant use of certain P-glycoprotein inhibitors) were present. Patients in the enoxaparin/warfarin group received optimised standard of care such that those with International Normalized Ratio (INR) <2 began treatment with a minimum of one dose each of enoxaparin and warfarin before cardioversion and continued anticoagulation until therapeutic range (INR ≥2) was achieved. Enoxaparin was discontinued after a therapeutic range was obtained. The efficacy and safety outcomes were consistent to the overall study cohort independent of TEE-guided strategies for cardioversion, prior anticoagulation naïve status.