This editorial refers to ‘Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial’, by M.D. Ezekowitz et al., doi:10.1093/eurheartj/ehy148. In the presence of rising age-adjusted incidence and prevalence of atrial fibrillation (AF) worldwide,1 mounting evidence affirms the benefits of restoring sinus rhythm across a variety of outcomes, including heart failure progression and mortality.2,3 Since 2001, cardioversions in the United States have increased in parallel with the rise in AF-associated hospitalizations.4 This trend likely mirrors that of many industrialized countries. A large evidence gap exists regarding how best to minimize the risk of stroke and bleeding before and after cardioversion. Professional society guidelines recommend two general strategies for patients with AF ≥48 h or of indeterminate duration: (i) delayed cardioversion defined as therapeutic anticoagulation for 3–4 weeks prior to cardioversion and (ii) early cardioversion involving transoesophageal echocardiography (TEE)-guided immediate cardioversion, usually on therapeutic anticoagulation.5,6 However, the evidence supporting these strategies comes from the late 1990s and early 2000s, when vitamin K antagonists (VKA) were the only therapeutic option.7,8 The non-vitamin-K oral anticoagulants (NOACs) offer a potentially simplified approach to patient management for cardioversion. Subgroup analyses from the four pivotal AF trials (one open label (Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY)) and three double-blinded (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE), Global Study to Assess the Safety and Effectiveness of Endoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGEAF TIMI48), and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF))) have shown that thrombo-embolic and bleeding complications around the time of cardioversion are infrequent and similar in patients randomly assigned to a NOAC or warfarin.9–13 These post hoc studies evaluated the safety of cardioversions that occurred during the stroke prevention trials; most subjects were therefore on prolonged therapy preceding cardioversion. In addition, these analyses applied to a subgroup defined by a post-randomization event are inherently biased and confounded. Subsequently, in dedicated randomized controlled trials evaluating edoxaban (Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF)) and rivaroxaban (Explore the Efficacy and Safety of Once-daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Subjects With Nonvalvular Atrial Fibrillation Scheduled for Cardioversion (X-VERT)) in patients undergoing cardioversion for AF, stroke and bleeding rates were less than 1%, similar to warfarin.14,15 In this issue of the European Heart Journal, Ezekowitz et al. present findings from the Eliquis evaluated in acute cardioversion. coMpared to usuAl treatmeNts for AnTicoagulation in subjects with NVAF (EMANATE) trial, the results of which were presented as a late-breaking trial at the European Society of Cardiology 2017 Scientific Sessions.16 The study enrolled 1500 participants randomly assigned to open-label apixaban, using standard AF dosing criteria (age, body mass index, and creatinine), or to VKA/heparin therapy. Unlike X-VeRT (rivaroxaban) and ENSURE-AF (edoxaban), both of which excluded patients with AF of <48 h duration, EMANATE included patients with AF of any duration but excluded those having >48 h of anticoagulation. The EMANATE protocol specified either the administration of five doses of apixaban (to approach steady-state drug concentrations) or the use of a loading dose, a strategy not studied with other NOACs for cardioversion. Decisions about other medications, the timing of cardioversion, the format of cardioversion (electrical vs. pharmacological vs. both), and the use of TEE or computed tomography (CT) imaging were left to the discretion of the local investigator, as long as cardioversion was performed within 90 days of randomization. The baseline characteristics of the 1500 EMANATE patients were similar to those in the pivotal NOAC trials and cardioversion trials (age 65 ± 13 years; 34% women; CHA2DS2-VASc 2.4 ± 1.7). A majority of patients (62%) had no prior anticoagulation therapy. In 45% of those randomized to apixaban, a loading dose was used at physicians’ discretion. Among patients cardioverted, TEE or CT guidance was used in similar proportions in the apixaban and warfarin groups (75–78%), although such guidance was most common (88%) in patients who received an apixaban loading dose. As expected, very few embolic and bleeding events occurred: 6 strokes (6 apixaban vs. 0 heparin/VKA), no systemic emboli, 3 deaths (2 vs. 1), 9 major bleeds (3 vs. 6), and 24 clinically relevant non-major bleeds (11 vs. 13). The authors conclude that ‘the rates of thrombo-embolic events, deaths, and bleeds were low for both treatment groups’, an appropriate and prudent interpretation since the study had neither a pre-specified hypothesis or a sample size powered for the anticipated small effect size. Beyond the top-line results, additional valuable data help bridge the evidence gap in the use of NOACs in cardioversion. First, of 855 enrolled subjects who received TEE or CT imaging, 61 (7.1%) had thrombus present, a prevalence consistent with contemporary TEE series.17,18 Second, among those with thrombus who underwent repeat imaging (in 37 ± 14 days), the rate of persistent clot was similar with apixaban (11 of 23 patients; 48%) and warfarin (8 of 18 patients; 44%). The fact that approximately half of patients still had a persistent clot suggests that further study is needed to determine the optimal duration of anticoagulation therapy before repeat imaging, regardless of the oral anticoagulant used. Third, the numerically similar bleeding risk of the apixaban loading dose group provides some assurance of safety. Take home figure View largeDownload slide The Evidence Base for non-vitamin-K oral anticoagulants (NOACs) and cardioversion for atrial fibrillation. Take home figure View largeDownload slide The Evidence Base for non-vitamin-K oral anticoagulants (NOACs) and cardioversion for atrial fibrillation. Some important caveats must be applied to the EMANATE findings, most notably the absence of pre-specified hypothesis testing. Similar to the X-VeRT and ENSURE AF investigators, the EMANATE investigators correctly concluded that a study adequately powered to detect meaningful treatment differences, or to support superiority or non-inferiority designs, would have to be prohibitively large, requiring upwards of 25,000 participants. This number is mainly driven by the low event rate derived from observational studies with heparin/VKA therapy and analyses of subgroups that underwent cardioversion procedures in the pivotal randomized controlled NOAC studies. Still, the EMANATE data add important information to a growing body of evidence for the use of NOACs in patients undergoing cardioversion. In our opinion, the totality of the evidence supports both VKA/heparin and NOAC therapy providing adequate anticoagulation to minimize thrombo-embolic events in the setting of cardioversion. Intuitively, the NOACs are easier to manage compared with either VKA-based Regimen chronically or a VKA/heparin strategy acutely, although no empiric data have been published on processes of care metrics, economic evaluations, or patient-reported outcomes following cardioversion. For now, the management of anticoagulant therapy in patients with planned cardioversion should continue to adhere to current practice guidelines. Both guidelines recommend anticoagulation for 3 weeks prior to cardioversion and for at least 4 weeks after. For AF duration longer than 48 h, imaging can exclude cardiac thrombus for cardioversion before 3 weeks of anticoagulation therapy. The American College of Cardiology/American Heart Association/Heat Rhythm Society guidelines from 2014 specifically recommend anticoagulation with dabigatran, rivaroxaban, or apixaban for at least 3 weeks in those with AF duration >48 h (Class of Recommendation IIa; Level of Evidence C).5 The European Society of Cardiology guidelines from 2016 state that ‘ongoing studies will inform about the safety and efficacy of newly initiated anticoagulation using NOACs in patients scheduled for cardioversion’.6 There are practical challenges with completing these types of studies. EMANATE took 2.6 years to recruit 1500 participants in 12 countries and 134 centers. ENSURE AF recruited 2199 participants in 239 sites in 19 countries over 1.6 years. X-VeRT enrolled 1504 participants in 141 sites in 16 countries over 1 year. The clinical and research communities need to partner with patients to create more efficient strategies for answering questions regarding disease states that are common for which there are important evidence gaps. Dedicated pragmatic disease registries, leveraging large health system electronic health records, or claims data approaches are needed to efficiently identify potential patients and to collect demographic, procedural, and outcome data. This approach would also allow investigation to further refine our understanding of many evidence gaps in AF management including optimal rate and rhythm control, imaging for cardioversion and ablation, improving medication adherence, stroke risk during periods of sinus rhythm, and, finally, how shared decision-making is approached between provider and patient. Despite the caveats, the EMANATE study has provided useful information about anticoagulation in patients with planned cardioversion, particularly patients with less than 48 h of anticoagulation therapy prior to enrollment. Very low event rates for important clinical thrombo-embolic and bleeding outcomes were observed with both apixaban and VKA/heparin strategies, consistent with previous apixaban studies and those of other NOACs. Although there are still gaps in the evidence, EMANATE sheds new light on options for managing patients with AF and planned cardioversion. Conflict of interest: K.W.M.’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Outside of the submitted work, M.P.T. reports research support from Janssen, AstraZeneca, Medtronic, Apple, the American Heart Association, Cardiva Medical, Boehringer Ingelheim, and a pending grant from Bristol Myers Squibb; personal fees from Medtronic, Abbott, Precision Health Economics, iBeat, Cardiva, Medscape; and equity in AliveCor, iBeat, Forward, Zipline Medical, and CyberHeart. M.P.T. is an editor for JAMA Cardiology. The content and opinions expressed are solely the responsibility of the authors and do not necessarily represent the views or policies of the Department of Veterans Affairs. References 1 Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim Y-H, McAnulty JH, Zheng Z-J, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJL. Worldwide epidemiology of atrial fibrillation: A Global Burden of Disease 2010 Study. Circulation 2014; 129: 837– 847. 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Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: Jun 4, 2018
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