The cardiac diagnostic work-up in stroke patients—A subanalysis of the Find-AFRANDOMISED trial
The cardiac diagnostic work-up in stroke patients-A subanalysis of the Find- AFRANDOMISED trial
Katrin Wasser 0 2
Mark Weber-Kru? ger 2
Falko J u?rries 2
Jan Liman 0 2
Gerhard F. Hamann 2
Pawel Kermer 2
Timo Uphaus 2
Evgeny Protsenko 2
Joachim Seegers 1 2
Meinhard Mende 2
Klaus Gr o?schelID 2
Rolf WachterID 2
0 Clinic for Neurology, University of Go ? ttingen , G o ?ttingen, Germany , 2 Clinic for Cardiology and Pneumology, University of Go ? ttingen , G o ?ttingen, Germany, 3 Clinic for Neurology and Neurorehabilitation, Bezirkskrankenhaus G u ?nzburg, Gu ? nzburg, Germany , 4 Clinic for Neurology, Nordwest-Krankenhaus Sanderbusch , Sande, Germany, 5 Clinic and Polyclinic for Neurology , University of Mainz , Mainz , Germany
1 Department of Internal Medicine II, Division of Cardiology, University Hospital Regensburg , Regensburg, Germany , 7 Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University Hospital Leipzig , Leipzig, Germany , 8 Clinic and Policlinic for Cardiology, University Hospital Leipzig , Leipzig, Germany, 9 DZHK ( German Centre for Cardiovascular Research) , partner site Go ? ttingen , Germany
2 Editor: Iratxe Puebla, Public Library of Science , UNITED KINGDOM
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: The Find-AFRANDOMISED trial (NCT
01855035) was sponsored by an unrestricted
research grant from Boehringer Ingelheim to the
University of Go?ttingen, Germany. The funders had
no role in study design, data collection and
analysis, decision to publish, or preparation of the
The cardiac diagnostic workup of stroke patients, especially the value of echocardiography
and enhanced and prolonged Holter-ECG monitoring, is still a matter of debate. We aimed
to analyse the impact of pathologies detected by echocardiography and ECG monitoring on
therapeutic decisions and prognosis.
Find-AFRANDOMISED was a prospective multicenter study which randomised 398 acute
ischemic stroke patients
60 years to enhanced and prolonged Holter-ECG monitoring or
usual stroke unit care. This substudy compared therapeutic consequences of
echocardiography and routine Holter-ECG or enhanced and prolonged Holter-ECG monitoring,
respectively, and prognosis of patients with or without pathologic findings in echocardiography or
50.3% received enhanced and prolonged Holter-ECG monitoring and 49.7% routine ECG
monitoring. 82.9% underwent transthoracic echocardiography (TTE), 38.9%
transesophageal echocardiography (TEE) and 25.6% both procedures. 14/89 TEE pathologies and 1/90
TTE pathology led to a change in therapy, resulting in a number needed to change decision
(NNCD) of 12 and 330 (p < 0.001), respectively. In comparison, enhanced and prolonged
Holter-ECG monitoring found atrial fibrillation (AF) in 27 of 200 patients, and routine ECG
Competing interests: We declare that MW-K and
EP report grants from Boehringer Ingelheim,
during the conduct of the study. JL reports
personal fees from Pfizer and grants from
Boehringer Ingelheim. PK reports grant and
personal fees from Boehringer Ingelheim, personal
fees from Bayer and Bristol-Myers Squibb. KG
reports personal fees and non-financial support
from Bayer, personal fees and non-financial
support and grant from Boehringer Ingelheim,
personal fees from Bristol-Meyers Squipp and
Daiichi Sankyo, personal fees and non-financial
support from Pfizer. RW reports having been an
investigator or consultant for, or received fees from
Bayer, Berlin Chemie, Bristol-Myers- Squibb,
Boehringer Ingelheim, Boston Scientific, CVRx,
Gilead, Johnson & Johnson, Medtronic, Novartis,
Pfizer, Relypsa, Sanofi, Servier since 2003. He
received research grants from Boehringer
Ingelheim, European Union and
Bundesministerium fu?r Bildung und Forschung
(BMBF). This does not alter our adherence to PLOS
ONE policies on sharing data and materials.
monitoring in twelve of 198 patients, leading to therapeutic changes in all patients (NNCD 8
and 17, respectively, p < 0.001).
Most changes in therapeutic decisions were triggered by enhanced and prolonged
HolterECG monitoring, which should therefore play a more prominent role in future guidelines.
Echocardiography identifies a patient group at high cardiovascular risk, but rarely result in
therapeutic changes. Whether this patient group requires further cardiovascular workup
remains unknown. This should be further investigated by interdisciplinary neurocardiologic
teams and in appropriate future trials.
Ischemic stroke is one of the most common causes of disability and death worldwide and the
5-year-recurrence rate after a first brain ischemia is up to 30% . Therefore, a careful diag
nostic workup is needed to exclude potential stroke mechanisms that may result in therapeutic
changes. The American Heart Association/American Stroke Association (AHA/ASA) and the
European Stroke Organisation (ESO) agree on a standard of care, which includes continuous monitoring of vital parameters and neurologic status, systematic laboratory testing, cerebral imaging, extra- and transcranial Doppler and duplex sonography, 12-lead ECG and a minimum of 24-hour ECG-monitoring [2,3].
These recommendations of a relatively short period of ECG monitoring of these two most
cited guidelines are in contrast to the well-documented fact that enhanced and prolonged
Holter-ECG monitoring significantly improves the detection rate of paroxysmal AF [
is of crucial importance as it usually shifts the secondary prevention therapy from antiplatelet
drugs to oral anticoagulation (OAC) that is known to reduce the stroke risk by up to 64% on
an intention-to treat basis [
]. In contrast, the European Society of Cardiology (ESC) and a
consensus document of German cardiologists and neurologists recommend a duration
of > 72 hours for Holter-ECG monitoring after acute ischemic stroke [
It is uncontroversial that echocardiography can detect many potential cardiac sources of
embolism such as left atrial thrombus, patent foramen ovale, atrial septum aneurysm, valvular
or myocardial disease, endocarditis or cardiac tumors amongst others. Furthermore, it can
reveal other cardiac pathologies of potential therapeutic consequences such as wall motion
abnormalities or a reduced left ventricular function which potentially demands a change in
cardiologic therapy. Despite the fact that echocardiography can provide useful information,
the indication and optimal echocardiographic approach in the cardiac workup of ischemic
stroke are still unclear and not specifically addressed in current AHA/ASA guidelines [
The criteria for stroke unit certification by European Stroke Organisation (ESO) and German
Stroke Society (DSG) have required the availability of TTE and TEE . TTE is generally available, non-invasive, less personnel-intensive and cheap, whereas TEE is superior for evaluation of the aortic arch, left atrium, and atrial septum [12?14]. Therefore, DSG demands a minimum rate of 15% TEE of all stroke unit patients . Potential therapeutic consequences
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of pathologic echocardiographic findings vary from conservative therapies such as OAC or
antibiotics to percutaneous coronary or surgical intervention according to current guidelines.
But the net clinical benefit of TEE in stroke patients (i.e. how often does TEE lead to a change
in therapeutic management) is still unknown. Current literature investigated mostly only the
impact of echocardiographic pathologies in subgroups of stroke like cryptogenic stroke or
ESUS [16,17]. Accordingly, there are no specific recommendations for the use of echocardiog
raphy in other stroke subgroups in current guidelines [
]. Most therapeutic strategies
mentioned in guidelines are only limited to the treatment of cardiac sources of embolism and there
is a lack of clear strategies for the treatment of pathologies that are not directly linked to stroke,
Therefore, therapeutic decisions based on echocardiographic findings in stroke patients often
seem to underlie local in-house policies or are reduced to the treatment of pathologies that are
directly linked to stroke like cardiac sources of embolism, instead of treating all pathologies
that affect the well-being and survival or simply the prognosis of stroke patients.
In this subanalysis of the Find-AFRANDOMISED trial we aimed to analyse the impact of
pathologies detected by echocardiography and ECG monitoring on therapeutic decisions and
prognosis. We therefore investigated the number and types of pathologies detected by TTE or
TEE, routine or enhanced and prolonged Holter-ECG monitoring and analysed how often
these findings led to changes in neurologic or cardiologic therapeutic decisions. In addition,
we evaluated whether abnormal findings in both modalities (echocardiography and
ECG monitoring) may predict a worse prognosis represented by an increased one-year mortality in comparison to patients without pathologies in echocardiography or routine Holter-ECG or enhanced and prolonged Holter-ECG monitoring, respectively.
Study design and patient population
The local ethics committees (Go?ttingen, Mainz, Wiesbaden and Sanderbusch, Germany)
approved the protocol of the Find-AFRANDOMISED trial and all patients gave written informed
consent. Find-AFRANDOMISED was an investigator-initiated prospective, randomised,
controlled, open-label multicenter study that has been described in detail, recently (S1 Fig) [
In brief, we included patients 60 years with acute ischemic stroke irrespective of the stroke
aetiology. Exclusion criteria were a history or presence of AF, an ipsilateral carotid artery
stenosis 50% according to NASCET and an indication or contraindication for OAC.
Within seven days after an acute ischemic stroke, patients were admitted to a certified
stroke unit and received the routine aetiologic stroke workup including transthoracic and/or
transesophageal echocardiography according to local in-house policies. Patients were either
randomised to 30 total days of Holter-ECG-monitoring (10 days at randomization, after three
and after six months) or standard-of-care monitoring with 24-hour Holter- and/or telemetry
ECG according to local stroke unit protocols. All AF episodes were adjudicated by a blinded
endpoint committee and AF was defined as at least one episode 30 seconds duration [
Furthermore, all ECGs were screened for potential pacemaker indications, e.g. high-grade
atrioventricular blocks or extreme bradycardia amongst others. After randomisation to the
two ECG groups almost all study patients received either transthoracic or transesophageal
echocardiography or both. The type of echocardiography was chosen according to local
inhouse policies. Echocardiography was performed by investigators with 2 years of experience
according to the current guideline for the use of echocardiography in the evaluation of a
cardiac source of embolism [
]. The echocardiographers did not participate in any study specific
training and used classifications according to local standards. Pathologic echocardiographic
findings, which typically lead to a therapeutic consequence for patients, were a priori
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determined by an expert panel of cardiologists (R.W. and M. W.-K.). High-risk sources
according to the TOAST classification were left atrial (appendage) and ventricular thrombus,
myxoma and endocarditis. Medium-risk sources were patent foramen ovale (PFO) and atrial
septal aneurysm (ASA) [
]. Other echocardiographic findings considered to be relevant were
other severe valve diseases, ventricular or aortic aneurysm, aortic plaques, impaired left
ventricular ejection fraction (LVEF) and wall motion abnormalities (Table 1). All pathologies
were prospectively recorded into a predefined case report form (CRF). Potential therapeutic
consequences such as OAC, interventions or operations were assessed during the clinical
follow-ups after three, six and twelve months. Furthermore, adverse events, hospital admissions,
diseases, and medication were recorded.
Continuous values were expressed as mean +/- SD and nominal variables as count and per
centages. Comparisons of means were realized by t-test for independent samples. Median
values with the corresponding interquartile range (IQR) were computed for non-normally
distributed variables. For comparisons of categorical data we used two-tailed Chi-square
statistics with Yates? correction and Fisher?s exact test as appropriate.
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One-year survival data for patients with or without pathologic echocardiographic or ECG findings were depicted using the Kaplan-Meier method. To adjust for age and centre heterogeneity, we fitted mixed linear Cox model for time-to-event data with random intercept for centre.
For a straightforward interpretation we defined the measure "Number Needed to Change
Decision" (NNCD) as the average number of patients to be diagnosed in order to encounter
one for whom the treatment decision changes. NNCD is the inverse of the absolutefrequency.
Nonparametric 95% confidence intervals were calculated and tests were performed by simulation (n = 10,000).
All statistical analyses were performed using SPSS version 23.0 and higher (SPSS, Inc.) and
R. Significance level for two-tailed tests is defined 0.05.
Between May 8, 2013, and Aug 31, 2014, 2848 patients 60 years were admitted with an ICD
diagnosis I 63.x (cerebral infarction) in the four study centres. Out of this screening
population, 402 patients were enrolled and randomised to enhanced and prolonged Holter-ECG
monitoring and to usual care (Holter-) ECG monitoring. Usual care included telemetry in
95% of patients and Holter-ECG in 75% of patients. Main exclusion criteria were history of AF
or AF on admission ECG, ipsilateral ICA stenosis 50% according to NASCET criteria, and
indication or contraindication for oral anticoagulation. Four patients were erroneously
randomised because of unknown history of AF or a severe ipsilateral carotid artery stenosis and thus
the data of 398 patients were finally analysed. 200 patients were randomised to prolonged
Holter-ECG monitoring and 198 patients to standard-of-care monitoring.
Percentage of patients receiving transthoracic and transesophageal
TTE and TEE were performed according to local standards and the echocardiographic
modalities were distributed approximately equally among the two ECG randomisation groups. 113
enhanced and prolonged Holter-ECG monitoring patients (56.5%) and 115 usual care patients
(58.1%) received only TTE, 29 (14.5%) and 24 (12.1%) patients underwent only TEE and 51
patients of each group received both procedures (25.5% and 25.7%, respectively). Only 7
patients of the enhanced and prolonged Holter-ECG monitoring group (3.5%) and 8 patients
of the usual care group (4.1%) received neither TTE nor TEE (Fig 1).
The echocardiography rates differed between the four study centres, e.g. the percentage of patients receiving TEE ranged from 9 to 80% (Fig 2).
Baseline characteristics of all patients divided in the randomisation groups and subdivided
in four patient groups without echocardiography, with only TTE or TEE or both procedures,
respectively, are summarized in Table 2. The main difference was that a higher percentage of
patients with cardioembolism received TEE as compared to patients with other stroke
aetiologies (p < 0.001) and that TEE patients were significantly younger (p < 0.001).
Clinical consequences of diagnostic procedures
1. Rhythm monitoring: As reported previously, AF was detected in 27 of 200 patients (13.5%)
by enhanced and prolonged Holter-ECG monitoring in the intervention arm. [
] Twelve of
198 (6.1%) patients of the standard of care group had AF in routine ECGs. The older the
patients were, the more often atrial fibrillation was detected (see Table 3). OAC was
initiated in all patients. Four patients underwent pacemaker implantation within the follow-up
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Fig 1. Trial profile of the present analysis.
period. None of them received it because of the Holter-ECG monitoring. The number
needed to change decision (NNCD) was 8 for enhanced and prolonged monitoring (3x
10day Holter ECG, 95% CI = 5?12), 12 for the first 10-day Holter and 17 for usual care
(95% CI = 10?33).
2. Echocardiography: We found 179 pathologies in 112 patients receiving echocardiography:
90 pathologies were diagnosed using TTE and 89 using TEE. There were two patients with
five different pathologies, two with four pathologies, fifteen with three pathologies, 23 with
two pathologies and 70 patients with only one cardiac pathology. We detected 44 patients
with hypo- and/or akinesia of at least one myocardial segment (11.1%, 29 patients with only
hypokinesia and 15 patients with hypo- and akinesia), 40 patients with patent foramen
ovale (PFO) and / or atrial septal aneurysm (ASA) (10.1%, 7 patients with ASA only, 25
patients with PFO only and 8 patients with combined PFO and ASA), 34 patients with
aortic plaques (8.5%, varying from 1 to 18 plaques per patient) and 27 patients with a reduced
LVEF < 50% (6.8%, ranging from 15 to 49%). To reflect the age-dependency of pathologies
detected by echocardiography, we divided the study population into three age groups: (I) <
70 years, n = 131, (II) 70?75 years, n = 132, and (III) > 75 years (n = 135). The younger the
patients were the more often PFO and / or ASA was detected (p = 0.003), furthermore there
were trends towards an age-dependency of aortic aneurysm (p = 0.061) and wall motion
disorders (p = 0.094), see Table 3).
A high-risk source of cardiac thromboembolism was detected in four (1.0%) versus zero
patients by TEE and TTE, respectively. A medium-risk source of cardioembolism was found
in 40 patients (15.5%) by TEE, whereas none was detected by TTE.15 of all 383 patients who
underwent echocardiography (3.9%), were treated as a consequence of the echocardiographic
findings. Only one therapeutic decision was based on TTE. This corresponds to a rate of 0.3%
of all performed 330 TTEs (Number needed to change decision (NNCD) 330) and to a rate of
9.0% of all conducted 155 TEEs (NNCD 12). In twelve patients, the therapy shifted from
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Fig 2. Rates of echocardiographies in each study centre.
antiplatelet drugs to OAC, two patients underwent surgery and one patient received PFO
closure. Most patients who received OAC were patients with PFO and/or ASA. Anticoagulation
for PFO/ASA was mainly driven by centre policies (anticoagulation rates for PFO/ASA were
35.7%, 5.6%, 50.0%, 0.0% for centres 1?4, respectively). Therapy was shifted towards OAC
because of deep vein thrombosis in two patients and because of repeated strokes of unknown
cause in one case. Two patients had ASA only and were treated with OAC because of a right to
left shunt documented with TEE or bubble test, respectively.
A comparison between the changes of therapeutic regime based on the four diagnostic methods (TTE, TEE, enhanced and prolonged Holter-ECG monitoring and routine (24-hours) ECG or telemetry) is shown in Fig 3.
Prognosis of patients with pathologic ECG and echocardiography findings
17 study patients died within one year. Of those, 16 received echocardiographic examinations.
Three different echocardiographic pathologies were detected in these patients: wall motion
abnormalities in six patients, a reduced LVEF and aortic plaques each in three patients.
Patients with pathologic echocardiographic findings had a trend towards higher one-year mortality, whereas pathologic ECG findings were not associated with a higher age-adjusted one
7 / 14
Alln = 398 Enhanced and prolonged Holter-ECG monitoring, n = 200
no echocardio- only TTE only TEE TTE and TEE
graphy n = 7 done n = 113 done n = 29 done n = 51
74.7 (SD 5.5) 74.5 (SD 7.1) 68.7 (SD 68.5 (SD 6.6)
4 (57.1%) 51 (45.1%) 10 (34.5%) 20 (39.2%)
Usual care, n = 198
echocardiography n = 8
76.1 (SD 7.8)
year mortality (p = 0.076 vs. p = 0.71, see Fig 4). The death of all three patients with the
combination of reduced LVEF and wall motion abnormalities was classified as ?cardiovascular?.
We evaluated the diagnostic value of echocardiography in comparison to Holter-ECG
monitoring in patients with acute ischemic stroke 60 years with respect to therapeutic
consequences. While the study design allowed a randomised comparison between a strategy of
prolonged ECG monitoring and usual care ECG monitoring, the analysis regarding
echocardiography was based on observational non-randomised comparisons. Most therapeutic changes
were based on repeated prolonged ECG-monitoring by means of three 10-day Holter-ECGs
(13.5%). TEE and conventional monitoring led to a different therapy in 9.0% and 6.1%,
respectively. TTE was responsible only for one new therapeutic decision (0.3%). Furthermore, our
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Patients 70?75 years
(n = 132)
Fig 3. Rate of changes in therapeutic decisions based on echocardiography or ECG.
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Fig 4. Age-adjusted one-year mortality in dependency of the presence of pathologic echocardiographic or ECG findings.
data showed a trend towards higher one-year mortality in patients with abnormal
Previous studies have compared TEE and TTE. Similarly to our findings, the superiority of
TEE over TTE in the diagnostics of cardiac sources of thromboembolism was also demon
strated in two previous studies that observed a change of therapeutic regimen in 41% or 21.4%
of stroke patients because of TEE findings and 0% or 4.2% because of TTE findings [
The detection rate of high- or medium-risk sources of cardioembolism in our study (1.0% and
15.5%) was lower than previously reported (high-risk sources of cardioembolism in up to 10%
of patients [
] and medium-risk sources in up to 59.4% of all investigated patients [
Counterintuitive, patients? age does not seem to play an important role: whereas in a study
with patients < 50 years found a potential source of cardiac embolism in 30% by TEE and in
10% by TTE [
], a study, which included only patients 80 years, documented a source of
cardiac embolism in 35% of patients with TEE [
], which is higher in comparison to our data.
Differences in definitions of high- and medium-risk sources of cardioembolism and pre-selec
tion for TEE might explain the differences in detection rates of sources of cardiac embolism.
The most common reasons for therapeutic changes by echocardiography were PFO and
ASA in combination (n = 5), isolated PFO (n = 3) or isolated ASA (n = 2). The most common
therapeutic change was anticoagulation which is in line with previous trials. However, at
the time of the study, therapeutic recommendations for PFO and ASA recommended
anticoagulation in selected cases because three randomised trials CLOSURE-1, PC and RESPECT
] were negative for PFO closure. Recently, the CLOSE and the REDUCE study clearly
showed a benefit of PFO closure over medical management which will lead to a more
prominent role of TEE in the near future [
] and more patients with PFO being treated by
PFO closure. However, all patients in our study were aged 60 years and above whereas the patients in the randomised PFO trials were younger than 60 years. The detection of large PFOs by TTE may have had a major influence on the value of the procedure in terms of therapeutic consequences.
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The most common diagnostic finding by prolonged monitoring was detection of AF and all patients with AF were treated with OAC according to current guidelines. Other diagnostic findings (e. g. AV block, pauses) were rare and did not lead to direct therapeutic consequences.
There was a trend towards a higher mortality rate in patients with echocardiographic
pathologies. Wall motion abnormalities and a reduced LVEF were the most common
pathologies which are indicators of heart failure and/or coronary artery disease. This may easily
explain the increase in mortality risk. As a clinical consequence, the diagnostic workup in
stroke patients should not be limited to the identification of the most likely aetiology of the
occurred ischemic event, but consider the stroke patient as a patient at risk for other
cardiovascular morbidities. Closer interdisciplinary cooperation between neurologists and cardiologists
may have led to further diagnostic / therapeutic measures (e.g. cardiac catheterization,
revascularization) and a prospective trial investigating a more invasive evaluation of these patients
The one-year mortality did not differ significantly between the group of patients with and
without pathologic ECG findings. This may be explained by the high rate of anticoagulation of
detected AF cases.
The unique feature of our study is a head-to-head comparison of prolonged monitoring for
30 days in all patients in the intervention arm and echocardiographic data in 96% of the
patients. This head-to-head comparison clearly shows that prolonged monitoring leads to 50%
more therapeutic changes than TEE and 27fold more therapeutic changes than TTE. Hence,
prolonged monitoring should receive a more prominent role in the workup of stroke patients
in the future and a restriction to only 24 hours (as e.g. in the clinical construct of ESUS [
the guidelines of ESO or AHA/ASA [
]) cannot be recommended. Under conditions of cost
pressure or limited resources, predictors of increased AF prevalence and therefore possible
preselection criteria for prolonged ECG monitoring are age , left atrial size and function
], enhanced supraventricular ectopy [
], elevated levels of natriuretic peptides [
others. In contrast, there is not much literature about preselection criteria for
Strengths of our study include the randomised, controlled and prospective multicenter
study design and the four study centres representing rural, urban and teaching
hospitals/university hospitals. However, echocardiography rates differed widely between the centres which
limits generalisability and may reflect selection bias. The main reason for varying rates of TTE
and TEE is local in-house practice of the four study centers, which represent two university,
one large city and one hospital covering a rural area. It reflects different interpretations of the
current guidelines. Importantly, the German Stroke Society requires at least 15% of patients
with ischemic stroke to be investigated by transesophageal echocardiography. Furthermore,
large and potentially relevant interatrial shunts can also be detected by TTE after application
of a contrast agent. [
] Although performed in clinical practice, this approach was not
sufficiently evaluated in clinical trials at that point and was not prospectively documented in our
trial, but may lead to a more relevant role of TTE in the future.
One of the main limitations is our substudy design without a standardized algorithm and
without a randomization of the two echocardiographic modalities, which would have been
advantageous for the present question. Furthermore, our results were obtained in patients
aged 60 years. The prevalence of PFO is likely to be higher in younger stroke patients [
whereas the prevalence of AF is supposed to be higher in older patients [
], which might
partly explain the diagnostic superiority of repeated and prolonged Holter-ECG monitoring in
our study cohort. Additionally, although Find-AFRANDOMISED was a prospective randomised
11 / 14
trial, this analysis was not pre-specified and should therefore be considered descriptive and
In summary, our results show that enhanced and prolonged ECG-monitoring is the key
tool in the cardiac workup of ischemic stroke in patients older than 60 years and should
therefore play a more prominent role in future guidelines. Echocardiography of any type helps to
identify a subgroup of stroke patients at high cardiovascular risk. A better neurocardiologic
diagnostic and therapeutic collaboration and further appropriate trials are warranted.
S1 Fig. Find-AFRANDOMISED study protocol.
S1 Table. CONSORT checklist.
S2 Table. Raw data Find-AFRANDOMISED study subanalysis.
Conceptualization: Klaus Gro?schel, Rolf Wachter.
Formal analysis: Meinhard Mende.
Investigation: Katrin Wasser, Mark Weber-Kru?ger, Falko Ju?rries, Jan Liman, Gerhard F.
Hamann, Pawel Kermer, Evgeny Protsenko, Joachim Seegers, Klaus Gro?schel, Rolf
Supervision: Rolf Wachter.
Visualization: Katrin Wasser.
Writing ? original draft: Katrin Wasser.
Writing ? review & editing: Mark Weber-Kru?ger, Falko Ju?rries, Jan Liman, Gerhard F.
Hamann, Pawel Kermer, Timo Uphaus, Evgeny Protsenko, Joachim Seegers, Meinhard
Mende, Rolf Wachter.
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cohort study. Stroke 44 (12): 3357?3364. https://doi.org/10.1161/STROKEAHA.113.001884 PMID:
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