Comparative Effectiveness Study of Transthoracic and Transesophageal Echocardiography in Stroke
Conditions: Stroke, Acute
Sponsor: Universitätsklinikum Hamburg-Eppendorf

 
 
 
 
PD Dr. Götz Thomalla 
Department of Neurology 
University Medical Center Hamburg-Eppendorf 
thomalla@uke.de 
PD Dr. Renate Schnabel 
Clinical and Interventional Cardiology 
University Heart Center Hamburg 
r.schnabel@uke.de  
 
 
Study Protocol: 
Comparative 
Effectiveness 
Study 
of 
Transthoracic 
and 
Transesophageal Echocardiography in Stroke (CONTEST) 
 
Version 1.0 (16.01.2016) 
 
Summary: 
The Comparative Effectiveness Study of Transthoracic and Transesophageal Echocardiog-
raphy in Stroke (CONTEST) aims at assessing the diagnostic value of transesophageal 
echocardiography (TEE) and transthoracic echocardiography (TTE) with regards to treatment 
consequences in patients with acute ischemic stroke. For this purpose, we will perform a 
prospective multicenter diagnostic comparative effectiveness study. Patients with acute 
stroke will be studied by both TTE and TEE. Patients with already defined stroke etiology and 
determined secondary prevention will be excluded from the trial. Treatment relevant 
diagnostic findings will be identified by a central endpoint adjudication committee. In order to 
demonstrate a hypothesized 2% absolute increase in the number of treatment relevant 
diagnostic findings by TEE as compared to TTE, 880 stroke patients will be enrolled in six 
German stroke centers. CONTEST will allow answering the question whether and for which 
group of stroke patients TEE is indicated in addition to TTE. By this, the study will provide 
evidence to guide justified recommendations for echocardiography in acute stroke patients.  
 
Short Background 
Cardioembolism is the second most important cause of stroke following large artery 
atherosclerosis (Grau et al., 2010). While atrial fibrillation (AF) represents the most frequent 

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Protocol: Comparative Effectiveness Study of TTE and TEE in Stroke (CONTEST)  
[V1.0, 15.01.2016] 
cause of cardiac embolism, there are other cardiac causes of embolic stroke such as akinesia 
of the ventricular wall following myocardial infarction, left atrial or ventricular thrombus, 
endocarditis or rare findings like atrial myxoma and non-compaction cardiomyopathy. Thus, a 
thorough cardiac evaluation is an essential part of the diagnostic work-up of stroke patients. 
This usually includes echocardiography in a majority of patients, which can be done by either 
transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) with 
specific advantages and disadvantages of both techniques. Following expert opinion, it is 
obvious that TEE is indicated in special situations, e.g. in guiding cardioversion after short-
term anticoagulation or in suspected endocarditis if TTE is negative (Pepi et al., 2010). 
Beyond that the additional diagnostic benefit of TEE in acute stroke is unclear, particularly 
given the fact that for most of the diagnostic findings that may be better detected by TEE no 
clear therapeutic recommendation can be given. 
In the past years, several studies have tried to evaluate the diagnostic yield of TEE in acute 
stroke, but results are contradictory. In a sample of 824 stroke patients, in 95% of cases 
potential sources of cardiac embolism identified by TEE were also detected by TTE (Leung et 
al., 1995). Moreover, in the subgroup of 211 patients with sinus rhythm and normal TTE, TEE 
did not provide any findings that provided a clear indication for oral indication. In another 
study of 1.833 TEE examinations in stroke patients with sinus rhythm, in 3.4% of cases TEE 
findings leading to changes in treatment strategies for secondary prevention were reported 
(Cho et al., 2010). In a previous German study, TEE findings indicated oral anticoagulation in 
8% of 212 stroke patients with undetermined etiology (Harloff et al., 2006). This, however, 
included only a single case with positive indication for oral anticoagulation (left atrial 
thrombus) while for all other cases the indication for oral anticoagulation is debatable (e.g. left 
atrial spontaneous echo contrast or reduced flow velocity). 
National and international guidelines on acute stroke management do not provide clear 
recommendations as to the use of echocardiography in stroke patients. The latest guidelines 
form the European Stroke Organization (ESO) state that “Echocardiography is recommended 
in selected patients” (ESO, 2008). However, they do not provide any recommendation as to 
the choice of TTE or TEE. Guidelines on acute stroke management by the American Heart 
Association (AHA) do not mention echocardiography at all (Jauch et al., 2013).  
To summarize, based on the currently available evidence it is completely unclear in which 
stroke patients, if at all, TEE is indicated. It is particularly unclear in how many cases TEE will 
yield diagnostic findings that result in a change in the treatment regimen for acute treatment 
or secondary prevention. 
 
Aims and hypotheses 

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Protocol: Comparative Effectiveness Study of TTE and TEE in Stroke (CONTEST)  
[V1.0, 15.01.2016] 
CONTEST aims at assessing the diagnostic value of TEE and TTE with regards to treatment 
consequences in patients with acute ischemic stroke. By this, CONTEST will allow answering 
the question whether and for which group of stroke patients TEE is indicated in addition to 
TTE. We hypothesize that TEE will provide significantly more treatment relevant diagnostic 
findings than TTE. 
 
Study design and power calculation 
Study design, study population, inclusion / exclusion criteria 
CONTEST will be a prospective multicenter diagnostic comparative effectiveness study. 
Patients with acute stroke in whom echocardiography is indicated will be studied by TTE and 
TEE.  
Main inclusion criteria are: (1) acute ischemic stroke or TIA, (2) age ≥18 years, (3) informed 
consent. Patients with already defined stroke etiology and determined secondary prevention 
treatment strategy prior to echocardiography (e.g. atrial fibrillation, carotid artery stenosis, 
cervical artery dissection) will be excluded. 
 
Sample size calculation 
We hypothesize that TEE will provide 5% treatment relevant diagnostic findings as compared 
to 3% for TTE, resulting in an absolute difference of 2% (with assumed 3% findings by TEE 
only, 1% findings by TTE only, and 2% findings by both TEE and TTE). In order to achieve 
80% power to demonstrate this hypothesized effect using a two-sided McNemar test with 
alpha = 0.05, a sample of n=840 patients is needed. Accounting for ~5% possible drop-outs 
or incomplete data, we plan to enroll 880 stroke patients. 
 
Methods 
Study organization, participating sites 
The study will be organized and coordinated by the Department of Neurology, University 
Medical Center Hamburg-Eppendorf (UKE) together with the General and Interventional 
Cardiology, University Heart Center Hamburg (UHZ). Patients will be enrolled in six German 
stroke centers. TTE and TEE will be performed according to a standardized protocol across 
all centers. Consecutive patients referred to the Stroke Unit of each center will be screened 
for enrollment during the course of the study. 
 

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Protocol: Comparative Effectiveness Study of TTE and TEE in Stroke (CONTEST)  
[V1.0, 15.01.2016] 
Study coordination: 
• 
PD Dr. Götz Thomalla, Dept. of Neurology, University Medical Center Hamburg-
Eppendorf 
• 
PD Dr. Renate Schnabel, General and Interventional Cardiology, University Heart 
Center Hamburg 
 
Responsible biostatistician: 
• 
Eik Vettorazzi, Department of Medical Biometry and Epidemiology (Chair: Prof. Dr. K. 
Wegscheider), University Medical Center Hamburg-Eppendorf 
 
List of participating sites (Local Principal Investigator): 
• 
University Medical Center Hamburg Eppendorf and University Heart Center (PD Dr. 
Götz Thomalla and PD Dr. Renate Schnabel) 
• 
Albertinenkrankenhaus Hamburg (PD Dr. Michael Rosenkranz) 
• 
Klinikum Pinneberg, Pinneberg (Prof. Dr. Max Nedelmann) 
• 
Helios Klinikum Wuppertal (Prof. Dr. Stefan Isenmann) 
• 
Kreiskliniken Reutlingen (Dr. med. Frank Andres) 
• 
SRH Klinikum Karlsbad- Langensteinbach (Prof. Dr. med. Michael Fetter) 
 
Endpoints and endpoint adjudication 
Primary endpoint is the frequency of diagnostic findings that lead to a change in acute 
treatment or treatment for secondary prevention (e.g. surgery in case of myxoma, or oral 
anticoagulation in case of atrial thrombus). Treatment relevant diagnostic findings will be 
identified by a central endpoint adjudication committee comprising both cardiologists and 
neurologists. Secondary endpoints comprise the frequency of other major or minor risk 
factors for cardiac embolism detected by TTE or TEE. 
 
Statistical analysis 
Proportion of treatment relevant diagnostic findings will be compared between TTE and TEE 
using two-sided McNemar test with a significance level of 0.05. 
 
 

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Protocol: Comparative Effectiveness Study of TTE and TEE in Stroke (CONTEST)  
[V1.0, 15.01.2016] 
Milestones / Timeline 
Months 
Major Actions 
Milestones to be reached 
M01-03 
• Finalize study protocol 
• Ethics Committee submission 
• Set-up trial infrastructure 
• Final study protocol 
• Ethics approval 
M04-06 
• Initiate participating centers 
• Enroll first patient 
• Start endpoint adjudication 
• All centers initiated 
• First patient enrolled 
• 6-month progress report 
M07-09 
• Continue patient enrollment 
• Continue endpoint adjudication 
• First 440 patients enrolled 
M10-12 
• Continue patient enrollment 
• Continue endpoint adjudication 
• Endpoint adjudication completed 
for first 440 patients 
• 12-month progress report 
M13-15 
• Complete patient enrollment 
• Continue endpoint adjudication 
• 880 patients enrolled 
M16-18 
• Complete endpoint adjudication 
• Statistical analysis 
• Preparation of publication of 
results 
• Endpoint adjudication completed 
for all patients 
• Statistical analysis completed 
• Draft of publication of study results
 
 
 

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Protocol: Comparative Effectiveness Study of TTE and TEE in Stroke (CONTEST)  
[V1.0, 15.01.2016] 
References 
European Stroke Organization (ESO). Guidelines for management of ischaemic stroke and 
transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457-507. 
Cho HJ, Choi HY, Kim YD, Nam HS, Han SW, Ha JW, et al. Transoesophageal 
echocardiography in patients with acute stroke with sinus rhythm and no cardiac 
disease history. J Neurol Neurosurg Psychiatry 2010; 81: 412-5. 
Grau AJ, Eicke M, Biegler MK, Faldum A, Bamberg C, Haass A, et al. Quality monitoring of 
acute stroke care in Rhineland-Palatinate, Germany, 2001-2006. Stroke 2010; 41: 
1495-500. 
Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies after 
examination by transesophageal echocardiography in 503 patients with ischemic 
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