From the Atrial Fibrillation Network, Münster (P.K., A.G., U.S.), the Department of Cardiology, University Heart and Vascular Center Hamburg (P.K., T.T., N.B.), and the Institute of Medical Biometry and Epidemiology (A.-K.O., S.S., A.Z.), University Medical Center Hamburg-Eppendorf, and the German Center for Cardiovascular Research (DZHK) Partner Site Hamburg-Kiel-Lübeck (P.K., T.T., N.B.), Hamburg, the Department of Cardiology and Intensive Care Medicine, St. Vincenz Hospital Paderborn, Paderborn (A.G.), the Department of Neuroepidemiology, Institute for Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen, Essen (H.C.D.), and the Heart Center, Segeberger Kliniken, Bad Segeberg (M.B.) - all in Germany; the Institute of Cardiovascular Sciences (P.K.) and the Centre for Patient Reported Outcome Research, Institute of Applied Health Research, the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, and the NIHR Applied Research Collaboration West Midlands (M.C.), University of Birmingham, Birmingham, the Cardiovascular and Cell Sciences Research Institute, St. George's University of London, and Imperial College London, London (A.J.C.), the Cardiac Department, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford (K.R.), and Liverpool Centre for Cardiovascular Science at University of Liverpool, John Moores University, and Liverpool Heart and Chest Hospital, Liverpool (G.Y.H.L.) - all in the United Kingdom; Unità Operativa Complessa Cardiologia-Azienda Ospedale Università di Padova, Padua, Italy (E.B.); the Department of Medical Science, Uppsala University, Uppsala, and the Department of Cardiology, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro - both in Sweden (C.B.L.); the Department of Cardiology, Odense University Hospital, Odense, and the Department of Cardiology, Esbjerg Hospital-University Hospital of Southern Denmark, Esbjerg (A.B.), and the Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg (G.Y.H.L.) - all in Denmark; the Cardiology Department, Fernando Fonseca Hospital, Amadora, Portugal (N.C.); the Biostatistics Lab, School of Medicine, University of Crete (G.C.), and the Department of Cardiology, Heraklion University Hospital (E.S.), Heraklion, and the Biomedical Research Foundation Academy of Athens and Hygeia Hospitals Group, Athens (P.V.) - all in Greece; Medicine University Carol Davila, Colentina University Hospital, Bucharest, Romania (G.-A.D.); the Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam (J.R.G.), and the Departments of Cardiology and Physiology, Maastricht University, Maastricht (U.S.) - both in the Netherlands; the Department of Internal Medicine III, Cardiology and Angiology, Innsbruck Medical University, Innsbruck (W.D.), and the Department of Cardiology, Medical University of Graz, Graz (D.S.) - both in Austria; the National Institute of Cardiovascular Surgery, Academy of Medical Sciences of Ukraine, Kyiv (B.K.); the Department of Cardiology and Internal Disease, Medical University of Gdansk, Gdansk (A.L.), and the Department of Electrocardiology and Heart Failure, Leszek Giec Upper Silesian Medical Center, Katowice (R.S.) - both in Poland; the Cardiology Division, European Georges Pompidou Hospital, Paris (E.M.); the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); the Hospital Clinic, Universtitat de Barcelona, Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, and Centro de Investigacion Biomedica en Red Cardiovascular, Madrid - all in Spain (L.M.); the Department of Cardiology, University Hospital Antwerp, Edegem, Belgium (A.S.); the Cardiology Clinic, St. Anna University Hospital Sofia, Sofia Medical University, Sofia, Bulgaria (V.V.); and the Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic (D.W.).
N Engl J Med. 2023 Sep 28;389(13):1167-1179. doi: 10.1056/NEJMoa2303062. Epub 2023 Aug 25.
Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known.
We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.
The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year).
Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups. (Funded by the German Center for Cardiovascular Research and others; NOAH-AFNET 6 ClinicalTrials.gov number, NCT02618577; ISRCTN number, ISRCTN17309850.).
设备检测到的心房高频事件（AHREs）是通过植入式心脏设备检测到的心房心律失常。AHREs 类似于心房颤动，但很少见且短暂。在没有心房颤动（如常规心电图 [ECG] 记录）的患者中，AHREs 的发生是否证明开始抗凝是未知的。
我们进行了一项以事件为驱动的、双盲、双模拟、随机临床试验，涉及年龄在 65 岁或以上的患者，这些患者的 AHRE 持续至少 6 分钟，并且至少有一个额外的中风风险因素。患者以 1:1 的比例随机分配接受依度沙班或安慰剂。主要疗效结局是心血管死亡、中风或全身性栓塞的复合结局，在时间事件分析中进行评估。安全性结局是任何原因导致的死亡或大出血的复合结局。
分析人群包括 2536 名患者（依度沙班组 1270 名，安慰剂组 1266 名）。平均年龄为 78 岁，37.4%为女性，AHREs 的中位持续时间为 2.8 小时。该试验因安全性问题和依度沙班疗效无效的独立、非正式评估而提前终止，中位随访 21 个月。在试验终止时，计划的入组已经完成。依度沙班组中有 83 名患者（每患者年 3.2%）发生主要疗效结局事件，安慰剂组中有 101 名患者（每患者年 4.0%）发生（风险比，0.81；95%置信区间[CI]，0.60 至 1.08；P=0.15）。两组中风的发生率均约为每年每患者 1%。依度沙班组中有 149 名患者（每患者年 5.9%）发生安全性结局事件，安慰剂组中有 114 名患者（每患者年 4.5%）发生（风险比，1.31；95%CI，1.02 至 1.67；P=0.03）。在 2536 名患者中，有 462 名（总发生率 18.2%，每年每患者 8.7%）患者出现心电图诊断为心房颤动。
在通过植入设备检测到 AHREs 的患者中，与安慰剂相比，抗凝治疗依度沙班并未显著降低心血管死亡、中风或全身性栓塞的复合发生率，但导致死亡或大出血复合发生率增加。两组的中风发生率均较低。（由德国心血管研究中心等资助；NOAH-AFNET 6 临床试验.gov 编号，NCT02618577；ISRCTN 编号，ISRCTN17309850。）
