Finding atrial fibrillation in stroke patients: Randomized evaluation of enhanced and prolonged Holter monitoring—Find-AFRANDOMISED —rationale and design Mark Weber-Krüger, MD, a Götz Gelbrich, PhD, b,c Raoul Stahrenberg, MD, d Jan Liman, MD, e Pawel Kermer, MD, f Gerhard F. Hamann, MD, g Joachim Seegers, MD, h Klaus Gröschel, MD, i,j and Rolf Wachter, MD a ,j, on behalf of the Find-AFRANDOMISED investigators Göttingen, Würzburg, Northeim, Sande, Günzburg, Regensburg and Mainz, Germany
Background Detecting paroxysmal atrial fibrillation (AF) in patients with ischemic strokes presenting in sinus rhythm is challenging because episodes are often short, occur randomly, and are frequently asymptomatic. If AF is detected, recurrent thromboembolism can be prevented efficiently by oral anticoagulation. Numerous uncontrolled studies using various electrocardiogram (ECG) devices have established that prolonged ECG monitoring increases the yield of AF detection, but most established procedures are time-consuming and costly. The few randomized trials are mostly limited to cryptogenic strokes. The optimal method, duration, and patient selection remain unclear. Repeated prolonged continuous Holter ECG monitoring to detect paroxysmal AF within an unspecific stroke population may prove to be a widely applicable, effective secondary prevention strategy. Study Design Find-AFRANDOMISED is a randomized and controlled prospective multicenter trial. Four hundred patients 60 years or older with manifest (symptoms ≥24 hours or acute computed tomography/magnetic resonance imaging lesion) and acute (symptoms ≤7 days) ischemic strokes will be included at 4 certified stroke centers in Germany. Those with previously diagnosed AF/flutter, indications/contraindications for oral anticoagulation, or obvious causative blood vessel pathologies will be excluded. Patients will be randomized 1:1 to either enhanced and prolonged Holter ECG monitoring (10 days at baseline and after 3 and 6 months) or standard of care (≥24-hour continuous ECG monitoring, according to current stroke guidelines). All patients will be followed up for at least 12 months. Outcomes
The primary end point is newly detected AF (≥30 seconds) after 6 months, confirmed by an independent adjudication committee. We plan to complete recruitment in autumn 2014. First results can be expected by spring 2016. (Am Heart J 2014;0:1-9.)
From the aClinic for Cardiology and Pneumology, University of Göttingen, Göttingen, Germany, b
Institute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany, Clinical Trial Centre, University of Würzburg, Würzburg, Germany, dHelios Albert-SchweitzerKliniken Northeim, Germany, eClinic for Neurology, University of Göttingen, Göttingen, Germany, f Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany, gDepartment of Neurology and Neurological Rehabilitation, Bezirkskliniken Günzburg, Germany, hDepartment of General Medicine II, University of Regensburg, Regensburg, Germany, and iClinic and Polyclinic for Neurology, University of Mainz, Mainz, Germany. c
j
These authors contributed equally and share senior authorship.
kSee online Appendix for complete listing of the Find-AF RANDOMISED investigators.
RCT No. NCT01855035. Disclosures: Find-AFRANDOMISED is sponsored by an unrestricted grant from Boehringer Ingelheim. Mark Weber-Krüger received a travel grant from Pfizer. Pawel Kermer serves as a member in advisory boards/received speaker's honoraria from Bayer Healthcare, Boehringer Ingelheim, and Bristol-MyerSquibb. Klaus Gröschel received speaker's honoraria from Boehringer Ingelheim, Bristol-Myer-Squibb, and Pfizer. Rolf Wachter received speaker's honoraria from Bayer Healthcare, Boehringer Ingelheim, Medtronic, and Pfizer. He acted as a local principal investigator in the CRYSTAL-AF study and is part of the Steering Committee of the Reveal-AF trial, both sponsored by Medtronic.Submitted January 28, 2014; accepted June 24, 2014. Reprint requests: Rolf Wachter, Clinic for Cardiology and Pneumology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. E-mail: [email protected] 0002-8703 © 2014, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.06.018
Background Atrial fibrillation (AF) is a frequent cause of ischemic strokes. Although diagnosing most other common etiologies of cerebral ischemia (macroangiopathy/microangiopathy, other sources of cardioembolism) is straightforward, detecting paroxysmal AF is challenging because episodes are often short, occur unpredictably, 1 and are frequently asymptomatic or accompanied by unspecific symptoms. 2 The thromboembolic risk is similar in paroxysmal and persistent AF, 3 and even short episodes of a few minutes are associated with higher rates of ischemic events. 4 Patients with AF-related strokes generally show more severe physical impairment 5 and worse outcomes 6 compared with strokes of other etiologies, but stroke severity is independent of the AF subtype. 7 In addition, the stroke recurrence risk in AF patients is increased 5-fold. 8 The clinical relevance of reliable AF documentation in stroke patients lies in the availability of an efficient secondary
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prevention therapy, that is, oral anticoagulation. 9,10 Several inconveniences and inconsistencies associated with the established vitamin K antagonists can be overcome by the new direct oral anticoagulants, which have proved to be effective alternatives regarding both the reduction of thromboembolism and relevant safety end points. 11 Numerous strategies and devices to detect paroxysmal AF are available today. There are intermittent, eventtriggered, and continuous monitoring procedures by means of externally applied 12 and implanted devices. Several observational trials showed that prolonged electrocardiogram (ECG) monitoring increases the yield of AF detection, 13 but there are only limited data from randomized trials. So far, 2 randomized trials have been published and 2 have been presented as conference papers. A singlecenter trial using a 21-day loop recorder versus clinical follow-up in 40 patients with cryptogenic strokes did not identify any AF in either trial arm. 14 A 2-center trial comparing a 7-day loop recorder to standard-of-care procedures in 100 unselected stroke patients detected AF in 18% versus 2%. 15 The multicenter trial “EMBRACE” included 578 patients with cryptogenic strokes, comparing a 30-day loop recording belt to repeated Holter ECG and found AF in 16% versus 3%. 16 The multicenter trial “CRYSTAL-AF” examined 441 patients with cryptogenic strokes, comparing long-term loop recording by means of an implanted device with standard-of-care procedures. It yielded 8.9% versus 1.4% AF within 6 months and 12.4% versus 2% AF within a year. 17 These trials provide highly relevant clinical data. However, they mostly represent a specific subpopulation with cryptogenic strokes and they applied specific loop recorders that are currently not available at most clinical sites. Therefore, it remains difficult to define the optimal method and duration for prolonged ECG monitoring after ischemic strokes in clinical practice.
Methods Study design The rationale and design of the randomized and controlled prospective multicenter trial “Find-AF RANDOMISED ” (NCT01855035) are based on the observational forerunner trial “Find-AF” (ISRCTN 46104198), which showed that 7day Holter ECG monitoring significantly increases the detection rate of paroxysmal AF in unselected patients with cerebral ischemia. 18 Find-AFRANDOMISED compares 2 diagnostic strategies: “Repeated enhanced and prolonged Holter ECG monitoring” (3 × 10 days, first recording early after index event) versus “standard-of-care” procedures, which, according to current stroke guidelines, 19 include a minimum of 24 hours of continuous ECG monitoring (stroke unit monitoring and/or Holter ECG, according to local standards). The patients are randomized 1:1 between both groups. The primary end point is the detection of AF/flutter within 6 months. An overview of the trial design is shown in the study flowchart (Figure 1).
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Patients 60 years or older with acute ischemic strokes (symptoms ≤7 days) are enrolled prospectively. According to the current stoke definition, patients have to show symptoms N24 hours and/or have an appropriate lesion on brain imaging. All patients with ECG documentation of or known AF/flutter prior to randomization are excluded. This also applies to the following: patients with preexisting indications or contraindications for oral anticoagulation, those with an obvious vascular pathology explanatory of the occurred ischemic event (significant carotid or vertebral artery stenosis N50% [North American Symptomatic Carotid Endarterectomy Trial classification], significant intracranial artery stenosis suspicious of atherosclerotic origin, or acute arterial dissection), those already undergoing prolonged ECG monitoring independent of study-related procedures (including implanted pacemakers and cardioverter/defibrillators), and those with a severe handicap prior to the index stroke event (modified Rankin Scale [mRS] score N2 20). Table shows the complete inclusion/exclusion criteria. Find-AFRANDOMISED is designed as an “all-comer” study. We plan to offer study participation to all consecutive patients meeting the inclusion and exclusion criteria. An independent expert committee will define the most likely etiology of all ischemic strokes qualifying as index or recurrent events. Another expert committee will evaluate all ECG episodes potentially resulting in a new diagnosis of AF/flutter.
Ethical conduct All persons participating in the conduct of the trial commit themselves to observe the latest issues of the Declaration of Helsinki, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practice and Committee for Proprietary Medicinal Products (CPMP)/ICH/135/95 (as far as applicable to this trial), as well as all pertinent national laws. All participating stroke centers will contact their local ethics committee to obtain approval. An informed consent form has to be signed by the patient or a legal representative before performing any study-related procedures. The trial intervention requires no specific medical treatment. Thus, all secondary stroke prevention therapies lie in the hands of the patients' treating physicians. Conduct and funding Find-AFRANDOMISED is investigator initiated (R.W. and K.G.). IFS Göttingen (Institut für anwendungsorientierte Forschung und klinische Studien) acts as the sponsor. The trial is supported by an unrestricted grant from Boehringer Ingelheim. All documented data are introduced into a secure eCRF database, which is provided, managed, and secured by IFS Göttingen. The authors are solely
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Figure 1
Study design flowchart.
responsible for the design and conduct of this study, the drafting and editing of the manuscript, and its final contents.
Study centers All 4 study sites contain large neurology departments with stroke units meeting the certification criteria of the German Stroke Society (www.dsg-info.de) and the German Society of Neurology. They represent different socioeconomic regions in Germany: one is a university hospital in a medium-sized city in central Germany (Göttingen), and another is a regional hospital that covers a large rural area in northern Germany (Sande). Two sites, a university hospital and a large city hospital, are located in the urban RhineMain metropolitan area (Mainz and Wiesbaden). Randomization Four hundred patients are randomized in a 1:1 ratio to either “repeated enhanced and prolonged ECG monitoring” or “standard-of-care.” The randomization is stratified by each participating center. Enhanced and prolonged Holter ECG monitoring Those randomized to “enhanced and prolonged Holter ECG monitoring” perform prolonged 10-day 2-channel Holter ECGs at baseline and after 3 and 6 months, using a commercially available 5-lead Holter ECG monitor (CardioMem 3000; getemed, Teltow, Germany). The intervention is repeated after 3 and 6 months, as previous trials showed that repetitive Holter ECGs can increase the yield of AF detection. 21,22 Only patients in the intervention group that cannot or refuse to repeat Holter ECG monitoring during follow-up visits are offered an alternative
thumb sensor ECG (Zenicor-EKG; Zenicor, Stockholm, Sweden), an approach that has been successfully tested within a cohort of stroke patients.23 These patients record at least two 30-second episodes on 10 consecutive days. All ECG recordings in the intervention arm are evaluated by a central core laboratory (led by J.S.). The pseudonymized recordings from each study site are stored on a secure data server at the University of Göttingen, Germany. The Holter evaluation follows a standard operating procedure: each 24-hour interval is fully analyzed, using the appropriate analysis software (CardioDay Version 2.4; getemed). Given sufficient quality, we follow a semiautomatic approach, reviewing all automatically detected premature atrial contractions (PACs), arrhythmias, and supraventricular (SV) tachycardias (as well as other relevant findings, e.g., ventricular events and pauses). Intervals with frequent artifacts or a very high PAC rate will be analyzed manually. Both methods ensure the exact quantification of occurring AF/flutter (number and duration of episodes, total burden) and the documentation of SV runs (N5 beats). The semiautomatic evaluation additionally allows the quantification of PACs. The Zenicor-EKG devices automatically transfer the recorded ECG to a secure server by mobile network transmission. These recordings are analyzed by the ECG core laboratory. Besides AF/flutter episodes, all occurring PACs and SV runs will be documented.
Definition and adjudication of AF/flutter Atrial fibrillation and atrial flutter are defined according to current guidelines, 24 including only episodes ≥30 seconds or long enough for a 12-lead ECG to be recorded.
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Table. Inclusion/exclusion criteria Inclusion criteria 1.
2. 3. 4.
Recent cerebral ischemia defined as stroke (sudden focal neurologic deficit lasting N24 h consistent with the territory of a major cerebral artery and categorized as ischemic) and/or a corresponding lesion on brain imaging Stroke symptoms started ≤7 d ago Age ≥60 y mRS ≤2 (prior to index event)
Exclusion criteria 1. 2. 3. 4. 5. 6. 7. 8. 9.
History of AF/flutter or documented AF/flutter prior to randomization Indication for oral anticoagulation at randomization Absolute contraindication for oral anticoagulation at randomization Intracerebral bleeding in medical history Patient scheduled for Holter ECG or cardiac event-recording monitoring ≥48 h Carotid artery stenosis of N50% (NASCET) needing revascularization and ipsilateral to ischemic territory Implanted pacemaker device or cardioverter/defibrillator Life expectancy b1 y for reasons other than stroke (eg, metastatic cancer disease) Concomitant participation in another randomized controlled trial
All episodes potentially resulting in a new diagnosis of AF/flutter after randomization, that is, those detected by means of study-specific Holter ECG or event monitoring, as well as those recorded during routine diagnostic workup (including ECGs from external centers) in both trials arms, will be evaluated by an independent AF end point adjudication committee, blinded to all clinical data: chair: Prof Dr D. Conen, Department of Medicine, University of Bern, Bern, Switzerland; co-chairs: Prof Dr M. Zabel, Clinic for Cardiology and Pneumology, University of Göttingen, Göttingen, Germany, and Prof Dr U. Laufs, Clinic for Cardiology, Angiology and the General Medicine Intensive Care Unit, University of Saarland, Homburg, Germany.
Stroke subtype adjudication All index and recurrent stroke events will be classified to define the most likely stroke etiology. For this purpose, stroke experts will be provided with pseudonymized data of individual stroke patients. These include results of clinical examinations and diagnostic test results (e.g., brain and vascular imaging) in order to classify ischemic strokes according to an established mechanism based classification system, such as the Trial of Org 10172 in Acute Stroke Treatment classification: chair: Prof Dr P. Heuschmann, Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany; co-chairs: Dr E. Jüttler, Clinic for Neurology, University of Ulm, Ulm, Germany, and PD Dr H. Poppert, Clinic and Polyclinic for Neurology, Technical University Munich, Munich, Germany.
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Baseline visit A detailed history of preexisting medical conditions is taken, and the current medication is documented. A physical examination including vital signs and evaluation of neurologic/physical deficits (expressed by the National Institute of Health Stroke Scale 25 and the mRS 20) is performed. The results of cerebral imaging (cerebral magnetic resonance imaging or cranial computed tomography), vascular imaging (sonographic Doppler/Duplex imaging, computed tomography angiography, or magnetic resonance angiography), echocardiography (transthoracic and/or transesophageal), 12-lead ECG, and standard laboratory are documented. In addition, the patient's quality of life (Stroke Impact Scale-16 and Hospital Anxiety and Depression Scale) and previous health care use (EQ5D and a self-designed questionnaire) are assessed by means of standardized questionnaires. A blood sample to evaluate various biomarkers is collected. The samples are frozen at −20°C (or −80°C, if possible) and are stored at the study center in Göttingen. Biomarker sampling will include various cardiovascular markers, such as N-terminal Propeptide of Brain Natriuretic Peptide, N-terminal Propeptide of Atrial Natriuretic Peptide, troponins, heart-type fatty acid– binding protein, and Growth Differentiation Factor 15. The remaining blood samples will be kept and stored for possible future evaluation of new specific approaches within this field of research. An overview of all study procedures is shown in Figure 2. Follow-up Clinical follow-up visits take place 3, 6, and 12 months after the index event. Information on recent morbidity (including a new diagnosis of AF/flutter), current medication, adverse events, and guideline adherence is collected. Vital signs, neurologic deficits (National Institute of Health Stroke Scale and mRS), quality of life (visits 1 and 3), and health care use (visits 2 and 3) are reassessed, and a second blood sample for biomarker measurement is collected (visit 1). Study outcomes The detection of AF/flutter within 6 months or before recurrence of cerebral or systemic thromboembolism is the primary end point of the trial. The secondary end points are subdivided into major and minor. Major secondary end points include the detection of AF/flutter (as defined for the primary outcome) within 12 months, the detection of AF/flutter (as defined for the primary outcome) censored by hospitalization for AF/flutter during follow-up, stroke recurrence within 12 months, and the total number of deaths within 12 months. Minor secondary end points will be the occurrence of cardiovascular death, cerebrovascular death, transitory ischemic attacks, myocardial infarction, and bleeding complications, as well as stroke-related disability, stroke by subtypes, quality of life, and health care
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Figure 2
Visit schedule.
use. The biomarker evaluation will not be part of the primary publication.
Statistical analysis The primary hypothesis is that enhanced and prolonged monitoring yields significantly more AF compared with the current standard-of-care procedures. The primary analysis of the detection of AF/flutter within both groups will be carried out using the log-rank test for the Kaplan-Meier estimates. Death, recurrent stroke, and systemic embolism will be considered censoring. This also applies to events (as stated above) that are potential consequences of AF/flutter, if the first diagnosis of AF/flutter is made simultaneously with the event or after it has taken place. This approach is explained by our aim to establish our intervention as a potential secondary prevention strategy, which will be considered to have failed, if a consecutive event occurs prior to or simultaneously with the detection of AF. The multiple binary logistic regressions for the documentation of AF/flutter will include the patient's age, stroke severity, the baseline CHADS2 score (a clinical score to estimate an AF patient's
risk of thromboembolism 26), the study arm, and the observation time as predictor variables. All analyses will follow the intention-to-treat principle. To rule out (unlikely) harm by the examined procedure, the 2-sided statistical alternative will be tested. All statistical analyses will be supervised by the trial's biometrician (G.G.).
Sample size discussion The sample size discussion is based on the forerunner trial “Find-AF.” Although the evaluation of every 24-hour Holter ECG interval yielded 3% to 5% newly diagnosed paroxysmal AF, the 7-day Holter ECG detected 12.5%. 18 With an additional 23 days of Holter recordings, we estimate the detection rate in the intervention arm to be at least 15%. We assume a dropout rate of 15%; thus, 340 of the 400 patients will be analyzed. This sample size would provide 83% power to distinguish between 15% (within the intervention arm) versus 5% (within the control arm) paroxysmal AF and 98% power to distinguish between detection rates of 20% versus 5%. Regarding published data, 13,21 our estimates appear rather conservative.
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Study schedule The enrolment of patients began on May 7th, 2013, after the approval of the responsible ethics committee. All 4 study centers started recruiting within 6 months. By May 31st, 2014, 316 patients had been randomized. We expect the recruitment phase to be closed by autumn 2014. The last patient's final visit will take place in autumn 2015. First study results can be expected by spring 2016.
Discussion To the best of our knowledge, Find-AFRANDOMISED is the first randomized controlled multicenter trial to compare repeated continuous enhanced and prolonged Holter ECG monitoring with current standard-of-care procedures in an unspecific stroke population. Detection of paroxysmal AF in stroke patients is highly relevant because strokes associated with AF show increased recurrence rates, 8 which are significantly reduced by changing the secondary prophylactic regime to oral anticoagulation. 9 Various published observational trials 13 and a small number of randomized trials 14–17 tested various ECG devices and approaches, and it has been established that prolonged ECG monitoring yields significantly more paroxysmal AF. Nevertheless, after reviewing the randomized data, several important aspects remain unclear and our approach of prolonged Holter ECG monitoring will provide important additional information to formulate clearer and more widely applicable recommendations for mode and duration of enhanced ECG monitoring after ischemic stroke.
Mode of AF detection There is a wide selection of external monitoring devices available today. 12 Event recorders are applied temporarily, whereas Holter ECGs and external loop recorders are worn constantly for a defined period. Holter ECGs provide continuous heart rhythm monitoring, whereas loop recorders only store suspicious episodes, mainly triggered by automatic detection algorithms. In addition, subcutaneously implanted loop recorders have been developed, which allow prolonged ECG monitoring of up to 3 years. At most clinical sites, patients receive continuous stroke unit monitoring, often followed by a 24-hour Holter ECG. The randomized trials tested relatively specialized loop recording devices, based on specific automatic AF detection algorithms. The main advantage of external loop recorders is the focus on suspicious episodes, which greatly reduces the workload involved. The detection algorithms work well under ideal conditions, 27 but their efficiency can be hampered by oversensing (muscle artifacts or cardiac arrhythmias such as
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frequent PACs, SV runs, or atrioventricular block) and undersensing (insufficient ECG signal). In the EMBRACE trial, a signal-to-noise rate of 1:19 was reported; thus, devices with limited storage capacities could replace true AF episodes by artifacts. Differences between the specific algorithms could partly explain the disparity between the reported AF detection rates (EMBRACE trial: 16% within 30 days; Higgins et al 15: 18% within 7 days; Kamel et al.: 0% within 21 days 14). Implanted devices have clear advantages in terms of monitoring duration. However, the approach is expensive and requires small surgical procedures for implantation and explantation, limiting a widespread use in clinical practice. Our approach of prolonged Holter ECG monitoring offers some advantages: as (24-hour) Holter monitoring is routinely applied at most clinical sites, staff is familiar with the method and no new expensive devices are required. Therefore, prolonged Holter ECG monitoring could be easily implemented into clinical practice. The cost-efficiency of this approach has already been established. 28,29 Unlike event-triggered intermittent recordings, a continuous ECG recording can allow a more substantiated diagnosis of AF: the beginning and ending of paroxysmal tachycardias are recorded, which helps to distinguish AF from other SV arrhythmias. Furthermore, even short AF episodes are captured and the exact duration and burden of AF can be quantified. The differentiation from other arrhythmias is further improved by the recording of 2 ECG channels (as provided by the Holter devices in our trial), which increases the likelihood of capturing a clear P wave. The core laboratory allows a standardized evaluation process and the quantification of the workload involved. Evaluating 3 × 10-day Holter ECGs is presumably the current maximum duration to be achieved under study conditions. The results will enable us to define the incremental value of prolonged and repeated ECG monitoring as well as the patients' acceptance of the procedure compared with high quality standard-ofcare monitoring.
Scientific value of prolonged continuous ECG monitoring Besides representing a practicable and cost-efficient approach, continuous prolonged ECG monitoring provides additional data that will be of high scientific value. Today's advanced ECG procedures reveal frequent SV runs (b30 seconds) in stroke patients, 30 the exact relevance of which remains unclear. The minimal duration of tachyarrhythmias leading to an increased thromboembolic risk has not yet been established. A recent prospective trial on atrial tachycardias recorded by implanted pacemakers or cardioverter/defibrillators found that episodes ≥6 minutes are associated with a 2.5-fold increased risk of embolic events. 4 However, a
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retrospective analysis of these data showed that there was no clear temporal relationship between the appearance of AF and the occurrence of thromboembolism in many cases. 31 The AF cutoff of ≥30 seconds within current AF guidelines 24 was chosen arbitrarily and is not based on concrete scientific data. It remains unknown whether SV runs b30 seconds impose an independent risk of thromboembolism, should be considered precursors of AF, are surrogates of manifest AF, or indicate cardiovascular disease in general. Our trial will provide detailed information on the frequency of SV runs in stroke patients and valid follow-up data.
Selection of stroke patients for intensified monitoring Most of the existing randomized data were collected from patients with cryptogenic strokes, presumably based on the intention to provide these patients with an explanation for the experienced event. However, there is no clear evidence that these patients specifically benefit from enhanced monitoring. On the contrary, patients with macroangiopathy or microangiopathy, which are excluded from the definition of a cryptogenic stroke, may have a particularly high risk of underlying paroxysmal AF, as AF shares several intersecting risk factors with atherosclerosis. By nature of the condition, AF is harder to detect and more often overseen. Importantly, AF detection still impacts the choice of secondary prevention therapy. Find-AFRANDOMISED includes patients with atherosclerosis, unless there is an obvious causative blood vessel pathology. As a secondary objective of the trial, we hope to provide stronger evidence on which subgroups effectively benefit from the enhanced monitoring procedures. Interestingly enough, our inclusion criteria strongly resemble those of upcoming trials evaluating the value of direct oral anticoagulants in patients with a new entity called “embolic stroke of unknown source” (ESUS 32). Importantly, these trials do not include enhanced ECG monitoring. This bears the risk of including a high proportion of patients with undetected AF, which will support a positive outcome of the trials. Hence, besides its primary intention, Find-AFRANDOMISED will also challenge the ESUS definition (based on limited ECG monitoring) by allowing an estimation of how many patients fulfilling the ESUS criteria have undetected paroxysmal AF.
Conclusions Find-AFRANDMISED is the first randomized controlled prospective multicenter trial comparing repeated enhanced and prolonged continuous Holter ECG monitoring with current standard-of-care procedures in an unspecific stroke population. Compared with methods applied in other randomized trials, our intervention may prove to be a more widely
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applicable approach that is both cost-efficient and effective, so our results will have an impact on future guidelines. Whether or not enhanced detection of paroxysmal AF in stroke patients results in a reduction of recurrent thromboembolic events after subsequent prescription of oral anticoagulation remains an essential question, which should be approached in another adequately powered prospective trial.
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Appendix. Members members of the FindAF randomised study group accordingly. Rolf Wachter, Klaus Gröschel, Mark Weber-Krüger, Pawel Kermer, Gerhard F. Hamann, Sven Klimpe, Jan Liman, Götz Gelbrich, Joachim Seegers, David Conen, Ulrich Laufs,
Weber-Krüger et al 9
Markus Zabel, Peter Heuschmann, Holger Poppert, Eric Jüttler, Janin Witzenhausen, Katrin Wasser, Anna Schulte, Falko Jürries, Anna Messerschmid, Anna-Lena Meyer, Anne Grings, Tugba Ibis, Timo Uphaus, Peter Bunders, Michaela Wagner-Heck, Jugoslav Erceg, Joachim Hüwel, Nadine Zahm, Kirsten Simon, Magdalena Arnold, Evgeny Protsenko.
Background Detecting paroxysmal atrial fibrillation (AF) in patients with ischemic strokes presenting in sinus rhythm is challenging because episodes are often short, occur randomly, and are frequently asymptomatic. If AF is detected, recurrent thromboembolism can be prevented efficiently by oral anticoagulation. Numerous uncontrolled studies using various electrocardiogram (ECG) devices have established that prolonged ECG monitoring increases the yield of AF detection, but most established procedures are time-consuming and costly. The few randomized trials are mostly limited to cryptogenic strokes. The optimal method, duration, and patient selection remain unclear. Repeated prolonged continuous Holter ECG monitoring to detect paroxysmal AF within an unspecific stroke population may prove to be a widely applicable, effective secondary prevention strategy. Study Design Find-AFRANDOMISED is a randomized and controlled prospective multicenter trial. Four hundred patients 60 years or older with manifest (symptoms ≥24 hours or acute computed tomography/magnetic resonance imaging lesion) and acute (symptoms ≤7 days) ischemic strokes will be included at 4 certified stroke centers in Germany. Those with previously diagnosed AF/flutter, indications/contraindications for oral anticoagulation, or obvious causative blood vessel pathologies will be excluded. Patients will be randomized 1:1 to either enhanced and prolonged Holter ECG monitoring (10 days at baseline and after 3 and 6 months) or standard of care (≥24-hour continuous ECG monitoring, according to current stroke guidelines). All patients will be followed up for at least 12 months. Outcomes
The primary end point is newly detected AF (≥30 seconds) after 6 months, confirmed by an independent adjudication committee. We plan to complete recruitment in autumn 2014. First results can be expected by spring 2016. (Am Heart J 2014;0:1-9.)
From the aClinic for Cardiology and Pneumology, University of Göttingen, Göttingen, Germany, b
Institute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany, Clinical Trial Centre, University of Würzburg, Würzburg, Germany, dHelios Albert-SchweitzerKliniken Northeim, Germany, eClinic for Neurology, University of Göttingen, Göttingen, Germany, f Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sande, Germany, gDepartment of Neurology and Neurological Rehabilitation, Bezirkskliniken Günzburg, Germany, hDepartment of General Medicine II, University of Regensburg, Regensburg, Germany, and iClinic and Polyclinic for Neurology, University of Mainz, Mainz, Germany. c
j
These authors contributed equally and share senior authorship.
kSee online Appendix for complete listing of the Find-AF RANDOMISED investigators.
RCT No. NCT01855035. Disclosures: Find-AFRANDOMISED is sponsored by an unrestricted grant from Boehringer Ingelheim. Mark Weber-Krüger received a travel grant from Pfizer. Pawel Kermer serves as a member in advisory boards/received speaker's honoraria from Bayer Healthcare, Boehringer Ingelheim, and Bristol-MyerSquibb. Klaus Gröschel received speaker's honoraria from Boehringer Ingelheim, Bristol-Myer-Squibb, and Pfizer. Rolf Wachter received speaker's honoraria from Bayer Healthcare, Boehringer Ingelheim, Medtronic, and Pfizer. He acted as a local principal investigator in the CRYSTAL-AF study and is part of the Steering Committee of the Reveal-AF trial, both sponsored by Medtronic.Submitted January 28, 2014; accepted June 24, 2014. Reprint requests: Rolf Wachter, Clinic for Cardiology and Pneumology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. E-mail: [email protected] 0002-8703 © 2014, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.06.018
Background Atrial fibrillation (AF) is a frequent cause of ischemic strokes. Although diagnosing most other common etiologies of cerebral ischemia (macroangiopathy/microangiopathy, other sources of cardioembolism) is straightforward, detecting paroxysmal AF is challenging because episodes are often short, occur unpredictably, 1 and are frequently asymptomatic or accompanied by unspecific symptoms. 2 The thromboembolic risk is similar in paroxysmal and persistent AF, 3 and even short episodes of a few minutes are associated with higher rates of ischemic events. 4 Patients with AF-related strokes generally show more severe physical impairment 5 and worse outcomes 6 compared with strokes of other etiologies, but stroke severity is independent of the AF subtype. 7 In addition, the stroke recurrence risk in AF patients is increased 5-fold. 8 The clinical relevance of reliable AF documentation in stroke patients lies in the availability of an efficient secondary
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prevention therapy, that is, oral anticoagulation. 9,10 Several inconveniences and inconsistencies associated with the established vitamin K antagonists can be overcome by the new direct oral anticoagulants, which have proved to be effective alternatives regarding both the reduction of thromboembolism and relevant safety end points. 11 Numerous strategies and devices to detect paroxysmal AF are available today. There are intermittent, eventtriggered, and continuous monitoring procedures by means of externally applied 12 and implanted devices. Several observational trials showed that prolonged electrocardiogram (ECG) monitoring increases the yield of AF detection, 13 but there are only limited data from randomized trials. So far, 2 randomized trials have been published and 2 have been presented as conference papers. A singlecenter trial using a 21-day loop recorder versus clinical follow-up in 40 patients with cryptogenic strokes did not identify any AF in either trial arm. 14 A 2-center trial comparing a 7-day loop recorder to standard-of-care procedures in 100 unselected stroke patients detected AF in 18% versus 2%. 15 The multicenter trial “EMBRACE” included 578 patients with cryptogenic strokes, comparing a 30-day loop recording belt to repeated Holter ECG and found AF in 16% versus 3%. 16 The multicenter trial “CRYSTAL-AF” examined 441 patients with cryptogenic strokes, comparing long-term loop recording by means of an implanted device with standard-of-care procedures. It yielded 8.9% versus 1.4% AF within 6 months and 12.4% versus 2% AF within a year. 17 These trials provide highly relevant clinical data. However, they mostly represent a specific subpopulation with cryptogenic strokes and they applied specific loop recorders that are currently not available at most clinical sites. Therefore, it remains difficult to define the optimal method and duration for prolonged ECG monitoring after ischemic strokes in clinical practice.
Methods Study design The rationale and design of the randomized and controlled prospective multicenter trial “Find-AF RANDOMISED ” (NCT01855035) are based on the observational forerunner trial “Find-AF” (ISRCTN 46104198), which showed that 7day Holter ECG monitoring significantly increases the detection rate of paroxysmal AF in unselected patients with cerebral ischemia. 18 Find-AFRANDOMISED compares 2 diagnostic strategies: “Repeated enhanced and prolonged Holter ECG monitoring” (3 × 10 days, first recording early after index event) versus “standard-of-care” procedures, which, according to current stroke guidelines, 19 include a minimum of 24 hours of continuous ECG monitoring (stroke unit monitoring and/or Holter ECG, according to local standards). The patients are randomized 1:1 between both groups. The primary end point is the detection of AF/flutter within 6 months. An overview of the trial design is shown in the study flowchart (Figure 1).
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Patients 60 years or older with acute ischemic strokes (symptoms ≤7 days) are enrolled prospectively. According to the current stoke definition, patients have to show symptoms N24 hours and/or have an appropriate lesion on brain imaging. All patients with ECG documentation of or known AF/flutter prior to randomization are excluded. This also applies to the following: patients with preexisting indications or contraindications for oral anticoagulation, those with an obvious vascular pathology explanatory of the occurred ischemic event (significant carotid or vertebral artery stenosis N50% [North American Symptomatic Carotid Endarterectomy Trial classification], significant intracranial artery stenosis suspicious of atherosclerotic origin, or acute arterial dissection), those already undergoing prolonged ECG monitoring independent of study-related procedures (including implanted pacemakers and cardioverter/defibrillators), and those with a severe handicap prior to the index stroke event (modified Rankin Scale [mRS] score N2 20). Table shows the complete inclusion/exclusion criteria. Find-AFRANDOMISED is designed as an “all-comer” study. We plan to offer study participation to all consecutive patients meeting the inclusion and exclusion criteria. An independent expert committee will define the most likely etiology of all ischemic strokes qualifying as index or recurrent events. Another expert committee will evaluate all ECG episodes potentially resulting in a new diagnosis of AF/flutter.
Ethical conduct All persons participating in the conduct of the trial commit themselves to observe the latest issues of the Declaration of Helsinki, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practice and Committee for Proprietary Medicinal Products (CPMP)/ICH/135/95 (as far as applicable to this trial), as well as all pertinent national laws. All participating stroke centers will contact their local ethics committee to obtain approval. An informed consent form has to be signed by the patient or a legal representative before performing any study-related procedures. The trial intervention requires no specific medical treatment. Thus, all secondary stroke prevention therapies lie in the hands of the patients' treating physicians. Conduct and funding Find-AFRANDOMISED is investigator initiated (R.W. and K.G.). IFS Göttingen (Institut für anwendungsorientierte Forschung und klinische Studien) acts as the sponsor. The trial is supported by an unrestricted grant from Boehringer Ingelheim. All documented data are introduced into a secure eCRF database, which is provided, managed, and secured by IFS Göttingen. The authors are solely
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Figure 1
Study design flowchart.
responsible for the design and conduct of this study, the drafting and editing of the manuscript, and its final contents.
Study centers All 4 study sites contain large neurology departments with stroke units meeting the certification criteria of the German Stroke Society (www.dsg-info.de) and the German Society of Neurology. They represent different socioeconomic regions in Germany: one is a university hospital in a medium-sized city in central Germany (Göttingen), and another is a regional hospital that covers a large rural area in northern Germany (Sande). Two sites, a university hospital and a large city hospital, are located in the urban RhineMain metropolitan area (Mainz and Wiesbaden). Randomization Four hundred patients are randomized in a 1:1 ratio to either “repeated enhanced and prolonged ECG monitoring” or “standard-of-care.” The randomization is stratified by each participating center. Enhanced and prolonged Holter ECG monitoring Those randomized to “enhanced and prolonged Holter ECG monitoring” perform prolonged 10-day 2-channel Holter ECGs at baseline and after 3 and 6 months, using a commercially available 5-lead Holter ECG monitor (CardioMem 3000; getemed, Teltow, Germany). The intervention is repeated after 3 and 6 months, as previous trials showed that repetitive Holter ECGs can increase the yield of AF detection. 21,22 Only patients in the intervention group that cannot or refuse to repeat Holter ECG monitoring during follow-up visits are offered an alternative
thumb sensor ECG (Zenicor-EKG; Zenicor, Stockholm, Sweden), an approach that has been successfully tested within a cohort of stroke patients.23 These patients record at least two 30-second episodes on 10 consecutive days. All ECG recordings in the intervention arm are evaluated by a central core laboratory (led by J.S.). The pseudonymized recordings from each study site are stored on a secure data server at the University of Göttingen, Germany. The Holter evaluation follows a standard operating procedure: each 24-hour interval is fully analyzed, using the appropriate analysis software (CardioDay Version 2.4; getemed). Given sufficient quality, we follow a semiautomatic approach, reviewing all automatically detected premature atrial contractions (PACs), arrhythmias, and supraventricular (SV) tachycardias (as well as other relevant findings, e.g., ventricular events and pauses). Intervals with frequent artifacts or a very high PAC rate will be analyzed manually. Both methods ensure the exact quantification of occurring AF/flutter (number and duration of episodes, total burden) and the documentation of SV runs (N5 beats). The semiautomatic evaluation additionally allows the quantification of PACs. The Zenicor-EKG devices automatically transfer the recorded ECG to a secure server by mobile network transmission. These recordings are analyzed by the ECG core laboratory. Besides AF/flutter episodes, all occurring PACs and SV runs will be documented.
Definition and adjudication of AF/flutter Atrial fibrillation and atrial flutter are defined according to current guidelines, 24 including only episodes ≥30 seconds or long enough for a 12-lead ECG to be recorded.
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Table. Inclusion/exclusion criteria Inclusion criteria 1.
2. 3. 4.
Recent cerebral ischemia defined as stroke (sudden focal neurologic deficit lasting N24 h consistent with the territory of a major cerebral artery and categorized as ischemic) and/or a corresponding lesion on brain imaging Stroke symptoms started ≤7 d ago Age ≥60 y mRS ≤2 (prior to index event)
Exclusion criteria 1. 2. 3. 4. 5. 6. 7. 8. 9.
History of AF/flutter or documented AF/flutter prior to randomization Indication for oral anticoagulation at randomization Absolute contraindication for oral anticoagulation at randomization Intracerebral bleeding in medical history Patient scheduled for Holter ECG or cardiac event-recording monitoring ≥48 h Carotid artery stenosis of N50% (NASCET) needing revascularization and ipsilateral to ischemic territory Implanted pacemaker device or cardioverter/defibrillator Life expectancy b1 y for reasons other than stroke (eg, metastatic cancer disease) Concomitant participation in another randomized controlled trial
All episodes potentially resulting in a new diagnosis of AF/flutter after randomization, that is, those detected by means of study-specific Holter ECG or event monitoring, as well as those recorded during routine diagnostic workup (including ECGs from external centers) in both trials arms, will be evaluated by an independent AF end point adjudication committee, blinded to all clinical data: chair: Prof Dr D. Conen, Department of Medicine, University of Bern, Bern, Switzerland; co-chairs: Prof Dr M. Zabel, Clinic for Cardiology and Pneumology, University of Göttingen, Göttingen, Germany, and Prof Dr U. Laufs, Clinic for Cardiology, Angiology and the General Medicine Intensive Care Unit, University of Saarland, Homburg, Germany.
Stroke subtype adjudication All index and recurrent stroke events will be classified to define the most likely stroke etiology. For this purpose, stroke experts will be provided with pseudonymized data of individual stroke patients. These include results of clinical examinations and diagnostic test results (e.g., brain and vascular imaging) in order to classify ischemic strokes according to an established mechanism based classification system, such as the Trial of Org 10172 in Acute Stroke Treatment classification: chair: Prof Dr P. Heuschmann, Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany; co-chairs: Dr E. Jüttler, Clinic for Neurology, University of Ulm, Ulm, Germany, and PD Dr H. Poppert, Clinic and Polyclinic for Neurology, Technical University Munich, Munich, Germany.
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Baseline visit A detailed history of preexisting medical conditions is taken, and the current medication is documented. A physical examination including vital signs and evaluation of neurologic/physical deficits (expressed by the National Institute of Health Stroke Scale 25 and the mRS 20) is performed. The results of cerebral imaging (cerebral magnetic resonance imaging or cranial computed tomography), vascular imaging (sonographic Doppler/Duplex imaging, computed tomography angiography, or magnetic resonance angiography), echocardiography (transthoracic and/or transesophageal), 12-lead ECG, and standard laboratory are documented. In addition, the patient's quality of life (Stroke Impact Scale-16 and Hospital Anxiety and Depression Scale) and previous health care use (EQ5D and a self-designed questionnaire) are assessed by means of standardized questionnaires. A blood sample to evaluate various biomarkers is collected. The samples are frozen at −20°C (or −80°C, if possible) and are stored at the study center in Göttingen. Biomarker sampling will include various cardiovascular markers, such as N-terminal Propeptide of Brain Natriuretic Peptide, N-terminal Propeptide of Atrial Natriuretic Peptide, troponins, heart-type fatty acid– binding protein, and Growth Differentiation Factor 15. The remaining blood samples will be kept and stored for possible future evaluation of new specific approaches within this field of research. An overview of all study procedures is shown in Figure 2. Follow-up Clinical follow-up visits take place 3, 6, and 12 months after the index event. Information on recent morbidity (including a new diagnosis of AF/flutter), current medication, adverse events, and guideline adherence is collected. Vital signs, neurologic deficits (National Institute of Health Stroke Scale and mRS), quality of life (visits 1 and 3), and health care use (visits 2 and 3) are reassessed, and a second blood sample for biomarker measurement is collected (visit 1). Study outcomes The detection of AF/flutter within 6 months or before recurrence of cerebral or systemic thromboembolism is the primary end point of the trial. The secondary end points are subdivided into major and minor. Major secondary end points include the detection of AF/flutter (as defined for the primary outcome) within 12 months, the detection of AF/flutter (as defined for the primary outcome) censored by hospitalization for AF/flutter during follow-up, stroke recurrence within 12 months, and the total number of deaths within 12 months. Minor secondary end points will be the occurrence of cardiovascular death, cerebrovascular death, transitory ischemic attacks, myocardial infarction, and bleeding complications, as well as stroke-related disability, stroke by subtypes, quality of life, and health care
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Figure 2
Visit schedule.
use. The biomarker evaluation will not be part of the primary publication.
Statistical analysis The primary hypothesis is that enhanced and prolonged monitoring yields significantly more AF compared with the current standard-of-care procedures. The primary analysis of the detection of AF/flutter within both groups will be carried out using the log-rank test for the Kaplan-Meier estimates. Death, recurrent stroke, and systemic embolism will be considered censoring. This also applies to events (as stated above) that are potential consequences of AF/flutter, if the first diagnosis of AF/flutter is made simultaneously with the event or after it has taken place. This approach is explained by our aim to establish our intervention as a potential secondary prevention strategy, which will be considered to have failed, if a consecutive event occurs prior to or simultaneously with the detection of AF. The multiple binary logistic regressions for the documentation of AF/flutter will include the patient's age, stroke severity, the baseline CHADS2 score (a clinical score to estimate an AF patient's
risk of thromboembolism 26), the study arm, and the observation time as predictor variables. All analyses will follow the intention-to-treat principle. To rule out (unlikely) harm by the examined procedure, the 2-sided statistical alternative will be tested. All statistical analyses will be supervised by the trial's biometrician (G.G.).
Sample size discussion The sample size discussion is based on the forerunner trial “Find-AF.” Although the evaluation of every 24-hour Holter ECG interval yielded 3% to 5% newly diagnosed paroxysmal AF, the 7-day Holter ECG detected 12.5%. 18 With an additional 23 days of Holter recordings, we estimate the detection rate in the intervention arm to be at least 15%. We assume a dropout rate of 15%; thus, 340 of the 400 patients will be analyzed. This sample size would provide 83% power to distinguish between 15% (within the intervention arm) versus 5% (within the control arm) paroxysmal AF and 98% power to distinguish between detection rates of 20% versus 5%. Regarding published data, 13,21 our estimates appear rather conservative.
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Study schedule The enrolment of patients began on May 7th, 2013, after the approval of the responsible ethics committee. All 4 study centers started recruiting within 6 months. By May 31st, 2014, 316 patients had been randomized. We expect the recruitment phase to be closed by autumn 2014. The last patient's final visit will take place in autumn 2015. First study results can be expected by spring 2016.
Discussion To the best of our knowledge, Find-AFRANDOMISED is the first randomized controlled multicenter trial to compare repeated continuous enhanced and prolonged Holter ECG monitoring with current standard-of-care procedures in an unspecific stroke population. Detection of paroxysmal AF in stroke patients is highly relevant because strokes associated with AF show increased recurrence rates, 8 which are significantly reduced by changing the secondary prophylactic regime to oral anticoagulation. 9 Various published observational trials 13 and a small number of randomized trials 14–17 tested various ECG devices and approaches, and it has been established that prolonged ECG monitoring yields significantly more paroxysmal AF. Nevertheless, after reviewing the randomized data, several important aspects remain unclear and our approach of prolonged Holter ECG monitoring will provide important additional information to formulate clearer and more widely applicable recommendations for mode and duration of enhanced ECG monitoring after ischemic stroke.
Mode of AF detection There is a wide selection of external monitoring devices available today. 12 Event recorders are applied temporarily, whereas Holter ECGs and external loop recorders are worn constantly for a defined period. Holter ECGs provide continuous heart rhythm monitoring, whereas loop recorders only store suspicious episodes, mainly triggered by automatic detection algorithms. In addition, subcutaneously implanted loop recorders have been developed, which allow prolonged ECG monitoring of up to 3 years. At most clinical sites, patients receive continuous stroke unit monitoring, often followed by a 24-hour Holter ECG. The randomized trials tested relatively specialized loop recording devices, based on specific automatic AF detection algorithms. The main advantage of external loop recorders is the focus on suspicious episodes, which greatly reduces the workload involved. The detection algorithms work well under ideal conditions, 27 but their efficiency can be hampered by oversensing (muscle artifacts or cardiac arrhythmias such as
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frequent PACs, SV runs, or atrioventricular block) and undersensing (insufficient ECG signal). In the EMBRACE trial, a signal-to-noise rate of 1:19 was reported; thus, devices with limited storage capacities could replace true AF episodes by artifacts. Differences between the specific algorithms could partly explain the disparity between the reported AF detection rates (EMBRACE trial: 16% within 30 days; Higgins et al 15: 18% within 7 days; Kamel et al.: 0% within 21 days 14). Implanted devices have clear advantages in terms of monitoring duration. However, the approach is expensive and requires small surgical procedures for implantation and explantation, limiting a widespread use in clinical practice. Our approach of prolonged Holter ECG monitoring offers some advantages: as (24-hour) Holter monitoring is routinely applied at most clinical sites, staff is familiar with the method and no new expensive devices are required. Therefore, prolonged Holter ECG monitoring could be easily implemented into clinical practice. The cost-efficiency of this approach has already been established. 28,29 Unlike event-triggered intermittent recordings, a continuous ECG recording can allow a more substantiated diagnosis of AF: the beginning and ending of paroxysmal tachycardias are recorded, which helps to distinguish AF from other SV arrhythmias. Furthermore, even short AF episodes are captured and the exact duration and burden of AF can be quantified. The differentiation from other arrhythmias is further improved by the recording of 2 ECG channels (as provided by the Holter devices in our trial), which increases the likelihood of capturing a clear P wave. The core laboratory allows a standardized evaluation process and the quantification of the workload involved. Evaluating 3 × 10-day Holter ECGs is presumably the current maximum duration to be achieved under study conditions. The results will enable us to define the incremental value of prolonged and repeated ECG monitoring as well as the patients' acceptance of the procedure compared with high quality standard-ofcare monitoring.
Scientific value of prolonged continuous ECG monitoring Besides representing a practicable and cost-efficient approach, continuous prolonged ECG monitoring provides additional data that will be of high scientific value. Today's advanced ECG procedures reveal frequent SV runs (b30 seconds) in stroke patients, 30 the exact relevance of which remains unclear. The minimal duration of tachyarrhythmias leading to an increased thromboembolic risk has not yet been established. A recent prospective trial on atrial tachycardias recorded by implanted pacemakers or cardioverter/defibrillators found that episodes ≥6 minutes are associated with a 2.5-fold increased risk of embolic events. 4 However, a
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retrospective analysis of these data showed that there was no clear temporal relationship between the appearance of AF and the occurrence of thromboembolism in many cases. 31 The AF cutoff of ≥30 seconds within current AF guidelines 24 was chosen arbitrarily and is not based on concrete scientific data. It remains unknown whether SV runs b30 seconds impose an independent risk of thromboembolism, should be considered precursors of AF, are surrogates of manifest AF, or indicate cardiovascular disease in general. Our trial will provide detailed information on the frequency of SV runs in stroke patients and valid follow-up data.
Selection of stroke patients for intensified monitoring Most of the existing randomized data were collected from patients with cryptogenic strokes, presumably based on the intention to provide these patients with an explanation for the experienced event. However, there is no clear evidence that these patients specifically benefit from enhanced monitoring. On the contrary, patients with macroangiopathy or microangiopathy, which are excluded from the definition of a cryptogenic stroke, may have a particularly high risk of underlying paroxysmal AF, as AF shares several intersecting risk factors with atherosclerosis. By nature of the condition, AF is harder to detect and more often overseen. Importantly, AF detection still impacts the choice of secondary prevention therapy. Find-AFRANDOMISED includes patients with atherosclerosis, unless there is an obvious causative blood vessel pathology. As a secondary objective of the trial, we hope to provide stronger evidence on which subgroups effectively benefit from the enhanced monitoring procedures. Interestingly enough, our inclusion criteria strongly resemble those of upcoming trials evaluating the value of direct oral anticoagulants in patients with a new entity called “embolic stroke of unknown source” (ESUS 32). Importantly, these trials do not include enhanced ECG monitoring. This bears the risk of including a high proportion of patients with undetected AF, which will support a positive outcome of the trials. Hence, besides its primary intention, Find-AFRANDOMISED will also challenge the ESUS definition (based on limited ECG monitoring) by allowing an estimation of how many patients fulfilling the ESUS criteria have undetected paroxysmal AF.
Conclusions Find-AFRANDMISED is the first randomized controlled prospective multicenter trial comparing repeated enhanced and prolonged continuous Holter ECG monitoring with current standard-of-care procedures in an unspecific stroke population. Compared with methods applied in other randomized trials, our intervention may prove to be a more widely
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applicable approach that is both cost-efficient and effective, so our results will have an impact on future guidelines. Whether or not enhanced detection of paroxysmal AF in stroke patients results in a reduction of recurrent thromboembolic events after subsequent prescription of oral anticoagulation remains an essential question, which should be approached in another adequately powered prospective trial.
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Appendix. Members members of the FindAF randomised study group accordingly. Rolf Wachter, Klaus Gröschel, Mark Weber-Krüger, Pawel Kermer, Gerhard F. Hamann, Sven Klimpe, Jan Liman, Götz Gelbrich, Joachim Seegers, David Conen, Ulrich Laufs,
Weber-Krüger et al 9
Markus Zabel, Peter Heuschmann, Holger Poppert, Eric Jüttler, Janin Witzenhausen, Katrin Wasser, Anna Schulte, Falko Jürries, Anna Messerschmid, Anna-Lena Meyer, Anne Grings, Tugba Ibis, Timo Uphaus, Peter Bunders, Michaela Wagner-Heck, Jugoslav Erceg, Joachim Hüwel, Nadine Zahm, Kirsten Simon, Magdalena Arnold, Evgeny Protsenko.
