Probing oral anticoagulation in patients with atrial high rate episodes: Rationale and design of the Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH–AFNET 6) trial

Background Oral anticoagulation prevents ischemic strokes in patients with atrial fibrillation (AF). Early detection of AF and subsequent initiation of oral anticoagulation help to prevent strokes in AF patients. Implanted cardiac pacemakers and defibrillators allow seamless detection of atrial high rate episodes (AHRE), but the best antithrombotic therapy in patients with AHRE is not known. Rationale Stroke risk is higher in pacemaker patients with AHRE than in those without, but the available data also show that stroke risk in patients with AHRE is lower than in patients with AF. Furthermore, only a minority of patients with AHRE will develop AF, many strokes occur without a temporal relation to AHRE, and AHRE can reflect other arrhythmias than AF or artifacts. An adequately powered controlled trial of oral anticoagulation in patients with AHRE is needed. Design The Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH–AFNET 6 ) trial tests whether oral anticoagulation with edoxaban is superior to prevent the primary efficacy outcome of stroke or cardiovascular death compared with aspirin or no antithrombotic therapy based on evidence‐based indications. The primary safety outcome will be major bleeding. NOAH–AFNET 6 will randomize 3,400 patients with AHRE, but without documented AF, aged ≥65 years with at least 1 other stroke risk factor, to oral anticoagulation therapy (edoxaban) or no anticoagulation. All patients will be followed until the end of this investigator‐driven, prospective, parallel‐group, randomized, event‐driven, double‐blind, multicenter phase IIIb trial. Patients will be censored when they develop AF and offered open‐label anticoagulation. The sponsor is the Atrial Fibrillation NETwork (AFNET). The trial is supported by the DZHK (German Centre for Cardiovascular Research), the BMBF (German Ministry of Education and Research), and Daiichi Sankyo Europe. Conclusion NOAH–AFNET 6 will provide robust information on the effect of oral anticoagulation in patients with atrial high rate episodes detected by implanted devices. Graphical abstract Figure. No Caption available.

[1]  Mårten Rosenqvist,et al.  Mass Screening for Untreated Atrial Fibrillation: The STROKESTOP Study , 2015, Circulation.

[2]  A. Brandes,et al.  Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT. , 2012, Heart rhythm.

[3]  Ulrich Schotten,et al.  2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS. , 2017, Revista espanola de cardiologia.

[4]  Frank Beckers,et al.  Cryptogenic stroke and underlying atrial fibrillation. , 2014, The New England journal of medicine.

[5]  Massimo Santini,et al.  Monitored atrial fibrillation duration predicts arterial embolic events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia pacemakers. , 2005, Journal of the American College of Cardiology.

[6]  S. Di Legge,et al.  Letter by Diomedi et al regarding article "continuous stroke unit electrocardiographic monitoring versus 24-hour holter electrocardiography for detection of paroxysmal atrial fibrillation after stroke". , 2013, Stroke.

[7]  D. Fitzmaurice,et al.  Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF , 2016, European heart journal.

[8]  K. Furie,et al.  A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. , 2001, The New England journal of medicine.

[9]  Christopher E Hilker,et al.  Incidence of Newly Detected Atrial Arrhythmias via Implantable Devices in Patients With a History of Thromboembolic Events , 2010, Stroke.

[10]  G. Breithardt,et al.  Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial , 2012, The Lancet.

[11]  A. Capucci,et al.  Presence and Duration of Atrial Fibrillation Detected by Continuous Monitoring: Crucial Implications for the Risk of Thromboembolic Events , 2009, Journal of cardiovascular electrophysiology.

[12]  Christopher E Hilker,et al.  Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data: a subgroup analysis of TRENDS. , 2011, Heart rhythm.

[13]  P. Kirchhof,et al.  The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification , 2014, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[14]  Stephan Willems,et al.  Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference 'research perspectives in AF'. , 2009, European heart journal.

[15]  Dongfeng Qi,et al.  The Relationship Between Daily Atrial Tachyarrhythmia Burden From Implantable Device Diagnostics and Stroke Risk: The TRENDS Study , 2009, Circulation. Arrhythmia and electrophysiology.

[16]  Hugh Calkins,et al.  2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. , 2014, Journal of the American College of Cardiology.

[17]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[18]  P. Kirchhof,et al.  Continuous Stroke Unit Electrocardiographic Monitoring Versus 24-Hour Holter Electrocardiography for Detection of Paroxysmal Atrial Fibrillation After Stroke , 2012, Stroke.

[19]  Daniel E. Singer,et al.  Device-detected atrial fibrillation and risk for stroke: an analysis of >10 000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices) , 2013, European heart journal.

[20]  Jun Zhu,et al.  Apixaban in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[21]  Paulus Kirchhof,et al.  Atrial fibrillation guidelines across the Atlantic: a comparison of the current recommendations of the European Society of Cardiology/European Heart Rhythm Association/European Association of Cardiothoracic Surgeons, the American College of Cardiology Foundation/American Heart Association/Heart Rhyt , 2013, European heart journal.

[22]  Alexander Parkhomenko,et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials , 2014, The Lancet.

[23]  G. Lip,et al.  Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study , 2016, British Medical Journal.

[24]  Shunichi Homma,et al.  Warfarin and aspirin in patients with heart failure and sinus rhythm. , 2012, The New England journal of medicine.

[25]  Á. Avezum,et al.  Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. , 2015, European heart journal.

[26]  David Moher,et al.  Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. , 2013, JAMA.

[27]  M. King,et al.  Patient-Reported Outcome (PRO) Assessment in Clinical Trials: A Systematic Review of Guidance for Trial Protocol Writers , 2014, PloS one.

[28]  Mark Levenson,et al.  Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation , 2015, Circulation.

[29]  R. Passman,et al.  Management of device-detected atrial high-rate episodes. , 2015, Cardiac electrophysiology clinics.

[30]  Gerhard Hindricks,et al.  Performance of a New Leadless Implantable Cardiac Monitor in Detecting and Quantifying Atrial Fibrillation Results of the XPECT Trial , 2010, Circulation. Arrhythmia and electrophysiology.

[31]  A. Camm,et al.  XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation , 2015, European heart journal.

[32]  R. Passman,et al.  Targeted Anticoagulation for Atrial Fibrillation Guided by Continuous Rhythm Assessment With an Insertable Cardiac Monitor: The Rhythm Evaluation for Anticoagulation With Continuous Monitoring (REACT.COM) Pilot Study , 2016, Journal of cardiovascular electrophysiology.

[33]  A. Capucci,et al.  Subclinical atrial fibrillation and the risk of stroke. , 2012, The New England journal of medicine.

[34]  M. Aguilar,et al.  Oral Anticoagulants Versus Antiplatelet Therapy for Preventing Stroke in Patients With Nonvalvular Atrial Fibrillation and No History of Stroke or Transient Ischemic Attacks , 2008 .

[35]  David Moher,et al.  SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials , 2013, BMJ.

[36]  Steven Swiryn,et al.  Clinical Implications of Brief Device-Detected Atrial Tachyarrhythmias in a Cardiac Rhythm Management Device Population: Results from the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes , 2016, Circulation.

[37]  Mårten Rosenqvist,et al.  Stepwise Screening of Atrial Fibrillation in a 75-Year-Old Population: Implications for Stroke Prevention , 2013, Circulation.

[38]  D. Atar,et al.  Apixaban versus warfarin in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[39]  Paulus Kirchhof,et al.  Prevalence of unknown atrial fibrillation in patients with risk factors. , 2013, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[40]  Theodor Landis,et al.  Usefulness of Ambulatory 7-Day ECG Monitoring for the Detection of Atrial Fibrillation and Flutter After Acute Stroke and Transient Ischemic Attack , 2004, Stroke.

[41]  E. Nøhr,et al.  Early detection of atrial high rate episodes predicts atrial fibrillation and thromboembolic events in patients with cardiac resynchronization therapy. , 2015, Heart rhythm.

[42]  R. Troughton,et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. , 2011, The New England journal of medicine.

[43]  David A Fitzmaurice,et al.  Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trial , 2007, BMJ : British Medical Journal.

[44]  A. Capucci,et al.  Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT , 2017, European heart journal.

[45]  E. Antman,et al.  Edoxaban versus warfarin in patients with atrial fibrillation. , 2013, The New England journal of medicine.

[46]  David J Gladstone,et al.  Atrial fibrillation in patients with cryptogenic stroke. , 2014, The New England journal of medicine.

[47]  G. Lamas,et al.  Atrial High Rate Episodes Detected by Pacemaker Diagnostics Predict Death and Stroke: Report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST) , 2003, Circulation.

[48]  G. Lip,et al.  Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial , 2007, The Lancet.

[49]  C. Israel,et al.  Prevalence, characteristics and clinical implications of regular atrial tachyarrhythmias in patients with atrial fibrillation: insights from a study using a new implantable device. , 2001, Journal of the American College of Cardiology.

[50]  G. Lip,et al.  Edoxaban versus enoxaparin–warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial , 2016, The Lancet.

[51]  A. Capucci,et al.  Temporal Relationship Between Subclinical Atrial Fibrillation and Embolic Events , 2014, Circulation.

[52]  T. Glotzer,et al.  Silent atrial fibrillation as a stroke risk factor and anticoagulation indication. , 2013, The Canadian journal of cardiology.

[53]  P. Kirchhof,et al.  2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. , 2016, European heart journal.

[54]  G. Lip,et al.  Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices. , 2015, European heart journal.

[55]  Christian Weimar,et al.  Improved Detection of Silent Atrial Fibrillation Using 72-Hour Holter ECG in Patients With Ischemic Stroke: A Prospective Multicenter Cohort Study , 2013, Stroke.

[56]  G. Breithardt,et al.  Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference. , 2012, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[57]  E. Ringelstein,et al.  Occult Atrial Fibrillation in Cryptogenic Stroke: Detection by 7-Day Electrocardiogram Versus Implantable Cardiac Monitors , 2013, Stroke.