Andreas Goette1, Jose L Merino2, Michael D Ezekowitz3, Dmitry Zamoryakhin4, Michael Melino5, James Jin6, Michele F Mercuri5, Michael A Grosso5, Victor Fernandez5, Naab Al-Saady7, Natalya Pelekh8, Bela Merkely9, Sergey Zenin10, Mykola Kushnir11, Jindrich Spinar12, Valeriy Batushkin13, Joris R de Groot14, Gregory Y H Lip15. 1. Cardiology and Intensive Care Medicine, St Vincenz-Hospital, Paderborn, Germany; Working Group: Molecular Electrophysiology, University Hospital Magdeburg, Magdeburg, Germany. Electronic address: andreas.goette@vincenz.de. 2. Arrhythmia and Robotic Electrophysiology Unit, Hospital Universitario La Paz, Universidad Europea, Madrid, Spain. 3. Department of Cardiovascular Medicine, Sidney Kimmel Jefferson Medical College at Thomas Jefferson University and Lankenau Medical Center, Broomall, PA, USA. 4. Cardiovascular Clinical Development, Daiichi Sankyo Development, Gerrards Cross, UK. 5. Clinical Development, Cardiovascular and Metabolism, Daiichi Sankyo Pharma Development, Edison, NJ, USA. 6. Biostatistics, Daiichi Sankyo Pharma Development, Edison, NJ, USA. 7. Cardiovascular/Metabolic, Covance, Maidenshead, UK. 8. Clinical Research, Covance, Kiev, Ukraine. 9. Semmelweis University Heart and Vascular Center, Budapest, Hungary. 10. State Budget Healthcare Institution of Novosibirsk region "Novosibirsk Region Clinical Cardiology Hospital", Novosibirsk, Russia. 11. Cardiology Department, Zhytomyr Regional Clinical Hospital, Chervonogo Khresta str Zhytomyr, Ukraine. 12. Fakultni nemocnice Brno, Brno, Czech Republic. 13. Cardiology and Intensive Care Department, Kiev City Clinical Hospital #5, Kiev, Ukraine. 14. Clinical Electrophysiology, Heart Center, Department of Cardiology, Academic Medical Center, Amsterdam, Netherlands. 15. University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
Abstract
BACKGROUND:Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparingedoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434. FINDINGS:Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA2DS2-VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status. INTERPRETATION: ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. FUNDING: Daiichi Sankyo provided financial support for the study.
RCT Entities:
BACKGROUND:Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434. FINDINGS: Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA2DS2-VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status. INTERPRETATION: ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. FUNDING: Daiichi Sankyo provided financial support for the study.