PRediction of Acute Coronary Syndrome in Acute Ischemic StrokE
Conditions: Stroke, Ischemic, Acute Coronary Syndrome
Sponsor: Charite University, Berlin, Germany

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               1 
 
 
Study protocol PRAISE 
 
 
Title:  
PRediction of Acute coronary syndrome in acute Ischemic StrokE (PRAISE) 
 
Responsible parties: 
Sponsor 
Charité-Universitätsmedizin Berlin, Centrum für Schlaganfallforschung Berlin, Charitéplatz 1, 10117 Berlin 
Study management/Principal Investigators 
Name 
Institution 
Funktion 
Prof. Dr. med. Matthias Endres 
Charité-Universitätsmedizin Berlin, Klinik 
für Neurologie 
Principal Investigator (PI) 
Prof. Dr. med. Ulf Landmesser 
Charité-Universitätsmedizin Berlin, Klinik 
für Kardiologie 
Co-Principial Investigator (PI) 
Prof. Dr. med. Christian H. 
Nolte 
Charité-Universitätsmedizin Berlin, Klinik 
für Neurologie 
Co-Principal Investigator (Co-
PI) 
Study coordinators 
Name 
Contact details 
Role 
Regina v. Rennenberg 
Charité-Campus Benjamin Franklin, Klinik für Neurologie 
Hindenburgdamm 30, 12203 Berlin 
E-Mail: regina-irene.freiin-von-rennenberg@charite.de 
Tel.: 030/8445-4285 
Fax: 030/8445-4264 
Study 
physician 
Dr. med. Hebun Erdur 
Charité-Campus Benjamin Franklin, Klinik für Neurologie 
Hindenburgdamm 30, 12203 Berlin 
E-Mail: hebun.erdur@charite.de 
Study 
physician 
 
Steering Committee 
Name 
Institution 
Prof. Dr. med. Matthias Endres 
Charité-Universitätsmedizin Berlin, Klinik für Neurologie 
Prof. Dr. med. Ulf Landmesser 
Charité-Universitätsmedizin Berlin, Klinik für Kardiologie 
Prof. Dr. med. Christian H. Nolte 
Charité-Universitätsmedizin Berlin, Klinik für Neurologie 
Prof. Dr. med. Burkert Pieske 
Charité-Universitätsmedizin Berlin, Klinik für Kardiologie 
Prof. Dr. med. Andreas Zeiher 
Universitätsklinikum Frankfurt, Klinik für Kardiologie 
Prof. Dr. med. Stefan Blankenberg 
Universitätsklinikum Hamburg-Eppendorf, Klinik für Kardiologie 
Prof. Dr. med. Vera Regitz-Zagrosek 
Charité-Universitätsmedizin Berlin, Institut für Geschlechterforschung 
in der Medizin 
Prof. Dr. med. Hugo A. Katus 
Universitätsklinikum Heidelberg, Klinik für Kardiologie, Angiologie und 
Pneumologie 
Prof. Dr. med. Martin Dichgans 
Klinikum der Universität München, Institut für Schlaganfall- und 
Demenzforschung 
Prof. Dr. med. Gabor Petzold 
Universitätsklinikum Bonn, Deutsches Zentrum für Neurodegenerative 
Erkrankungen 
Prof. Dr. rer. pol. Karl Wegscheider 
Universitätsklinikum Hamburg-Eppendorf, Institut für Medizinische 
Biometrie und Epidemiologie 
 
 
 
 
 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               2 
 
Core Laboratories 
Name 
Instution 
Funktion 
Prof. Dr. med. Ulf Landmesser 
PD Dr. med. David Leistner 
Charité-Universitätsmedizin Berlin, Klinik 
für Kardiologie, Campus Benjamin 
Franklin 
Core Laboratory for 
coronary angiography  
Prof. Dr. med. Burkert Pieske 
Dr. med. Elisabeth Pieske-Kraigher 
Charité-Universitätsmedizin Berlin, Klinik 
für Kardiologie, Campus Virchow-Klinikum 
Core Laboratory for 
echocardiography 
Prof. Dr. med. Wilhelm 
Haverkamp 
 
Core Laboratory for EKG 
Prof. Dr. med. Stefan Blankenberg 
Dr. med. Mahir Karakas 
Universitätsklinikum Hamburg-
Eppendorf, Klinik für Kardiologie 
Core Laboratory central 
measurement of troponin 
 
Endpoint Adjudication Committee 
Name 
Institution 
Prof. em. Dr. Dr. h.c. Günter Breithardt 
Universitätsklinikum Münster, Klinik für Kardiologie 
Prof. Dr. med. Raimund Erbel 
Universitätsklinikum Essen, Institut für Medizinische Informatik, 
Biometrie und Epidemiologie 
Prof. Dr. med. Stephan Gielen 
Klinikum Lippe, Klinik für Kardiologie 
 
Data Safety Monitoring Board (DSMB) 
Name 
Institution 
Prof. Dr. med. Peter Heuschmann 
Institut für klinische Epidemiologie und Biometrie, Würzburg 
Prof. Dr. med. Otto Busse 
Deutsche Schlaganfall-Gesellschaft, Stroke Unit 
Zertifizierungsausschuss, Berlin 
Prof. Dr. med. Nikolaus Marx 
Universitätsklinikum Aachen, Klinik für Kardiologie 
 
Crititcal Events Committee 
Name 
Institution 
PD med. Dr. Arash Haghikia 
Charité-Universitätsmedizin Berlin, Klinik für Kardiologie 
Dr. med. Christoph Leithner 
Charité-Universitätsmedizin Berlin, Klinik für Neurologie 
Dr. Andrea Rocco 
Charité-Universitätsmedizin Berlin, Klinik für Neurologie 
 
Study sites 
Name 
Institution 
Prof. Dr. med. Matthias Endres 
Prof. Dr. med. Ulf Landmesser 
Charité-Campus Benjamin Franklin, Klinik für Neurologie 
Charité-Campus Benjamin Franklin, Klinik für Kardiologie 
Prof. Dr. med. Matthias Endres 
Prof. Dr. med. Burkert Pieske 
Charité-Campus Virchow-Klinikum, Klinik für Neurologie 
Charité-Campus Virchow-Klinikum, Klinik für Kardiologie 
Prof. Dr. med. Matthias Endres 
Prof. Dr. med. Karl Stangl 
Charité-Campus Mitte, Klinik für Neurologie 
Charité-Campus Mitte, Klinik für Kardiologie 
Prof. Dr. med. Christian Gerloff 
Prof. Dr. med. Stefan Blankenberg 
Universitätsklinikum Hamburg-Eppendorf, Klinik für Neurologie 
Universitätsklinikum Hamburg-Eppendorf, Klinik für Kardiologie 
PD Dr. med. Georg Royl 
Prof. Dr. med. Ingo Eitel 
Universität zu Lübeck, Klinik für Neurologie 
Universität zu Lübeck, Klinik für Kardiologie 
Prof. Dr. med. Waltraud Pfeilschifter 
Prof. Dr. med. Andreas Zeiher 
Universitätsklinikum Frankfurt, Klinik für Neurologie 
Universitätsklinikum Frankfurt, Klinik für Kardiologie 
Prof. Dr. med. Gabor Petzold 
Prof. Dr. med. Georg Nickenig 
Universitätsklinikum Bonn, Klinik für Neurologie 
Universitätsklinikum Bonn, Klinik für Kardiologie 
Prof. Dr. med. Peter A. Ringleb 
Prof. Dr. med. Hugo A. Katus 
Universitätsklinikum Heidelberg, Klinik für Neurologie 
Universitätsklinikum Heidelberg, Klinik für Kardiologie 
Prof. Dr. med. Martin Dichgans 
Prof. Dr. med. Steffen Massberg 
Klinikum der Universität München, Klinik für Neurologie 
Klinikum der Universität München, Klinik für Kardiologie 
Prof. Dr. med. Jan Liman 
Prof. Dr. med. Gerd Hasenfuß 
Universitätsmedizin Göttingen, Klinik für Neurologie 
Universitätsmedizin Göttingen, Klinik für Kardiologie 
Dr. med. Annerose Mengel 
Universitätsklinikum Tübingen, Klinik für Neurologie 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               3 
 
Prof. Dr. med. Meinrad Paul Gawatz 
Universitätsklinikum Tübingen, Klinik für Kardiologie 
Prof. Dr. med. Agnes Flöel 
Prof. Dr. med. Stephan Felix 
Universitätsmedizin Greifswald, Klinik für Neurologie 
Universitätsmedizin Greifswald, Klinik für Kardiologie 
PD. Dr. med. Dominik Michalski 
Prof. Dr. med. Ulrich Laufs 
Universitätsklinikum Leipzig, Klinik für Neurologie 
Universitätsklinikum Leipzig, Klinik für Kardiologie 
PD Dr. med. Bernd Kallmünzer 
Prof. Dr. med. Stephan Achenbach 
Universitätsklinikum Erlangen, Klinik für Neurologie 
Universitätsklinikum Erlangen, Klinik für Kardiologie 
 
Study type:  
Multicenter observational prospective study with blinded endpoint evaluation  
 
Background: 
Cardiac troponins (i.e. I and T) are very sensitive and specific biomarkers used in clinical routine to 
detect cardiomyocyte damage. Elevation of cardiac troponins may indicate acute or chronic 
cardiomyocyte damage. An acute elevation of cardiac troponin with a dynamic change in serial 
measurements is often caused by an acute coronary syndrome due to a coronary culprit lesion1. 
Interestingly, many patients with acute ischemic stroke also have elevated troponin levels2. Depending 
on the assay and studied population, varying frequencies of elevated troponin levels in acute ischemic 
stroke patients have been reported in the literature. In acute ischemic stroke patients elevated 
troponin levels are associated with a higher rate of mortality and poor functional outcome3,4. 
This association is even more pronounced in patients with a dynamic change of troponin levels (so 
called <rise/fall pattern= indicating acute cardiomyocyte damage)5. Cardiac comorbidity is common in 
patients with cerebrovascular disease as both cardiac and cerebrovascular diseases share many 
common risk factors. Therefore, the current guideline of the American Heart Association (AHA) on the 
early management on acute ischemic stroke patients recommends routine measurement of troponin 
in patients with acute stroke6.  
Whether current algorithms for the diagnosis of acute coronary syndrome in patients with chest pain 
as described in the guideline of the European Society of Cardiology (ESC)12 also apply to patients with 
acute ischemic stroke remains unclear. Additionally, the diagnostic value of noninvasive tests (e.g. ECG, 
echocardiography, GRACE-Score13) in patients with acute ischemic stroke and troponin elevation 
remains unclear.  
Besides acute coronary syndrome, troponin elevation in acute ischemic stroke patients may also be 
caused by chronic cardiac diseases or even extracardiac diseases5. Additionally, some acute ischemic 
stroke patients, e.g. those with ischemic lesions located in the insula, may develop neurogenic 
myocardial injury with a phenotype similar to stress-induced cardiomyopathy7. The prospective 
TRELAS study showed that about 25% of ischemic stroke patients with a troponin elevation > 50 ng/l 
(hs-cTnT measured using the Roche Elecsys Assay)8 have a coronary culprit lesion9. A prospective 
observational study by Amarenco et al showed that coronary culprit lesions significantly increase 
mortality in acute ischemic stroke patients10. Therefore, these lesions should be diagnosed and treated 
appropriately. Due to the neurological deficit, acute ischemic stroke patients with acute coronary 
syndrome often do not present with the typical symptom of chest pain. Thus, clinicians treating stroke 
patients are confronted with a diagnostic and therapeutic dilemma. On the one hand, coronary 
angiography is the diagnostic gold standard to detect coronary culprit lesions11. The detection and 
treatment of a culprit lesion – if present – would likely improve the patient9s prognosis. On the other 
hand, coronary angiography is an invasive procedure that often requires additional antithrombotic 
treatment12. In acute ischemic stroke patients, antithrombotic treatment may increase the risk of 
intracerebral hemorrhage, which is why clinicians are often hesitant to perform coronary angiography 
in these patients. Therefore, it is important to be able to select acute ischemic stroke patients with a 
high pre-test variability for a coronary culprit lesion. The results of the TRELAS study9 suggest that a 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               4 
 
coronary culprit lesion is more common in acute ischemic stroke patients with dynamic troponin 
elevation compared to patients with stable troponin elevation. However, the sample size of the TRELAS 
study was too small to develop a clinically useful algorithm or cut-off values for the detection of acute 
coronary syndrome.  
 
In the general population, previous studies have found an association between higher troponin levels 
and poorer cognitive performance14. Higher troponin levels were especially associated with poorer 
executive function. Moreover, chronic heart failure is associated with cognitive decline15. This 
interaction between heart and brain has not been fully elucidated. In particular, it remains unclear 
whether a dynamic change of troponin levels is associated with poorer cognitive performance in 
patients with acute ischemic stroke.   
 
Study aims: 
The primary aim of the PRAISE study is to develop an algorithm for the prediction of acute coronary 
syndrome in acute ischemic stroke patients using non-invasive diagnostic tests. In order to improve 
prediction of acute coronary syndrome in patients with acute ischemic stroke, serial troponin 
measurements, ECG, echocardiography, GRACE score and clinical symptoms will be evaluated 
systematically and prospectively for the first time. Moreover, we aim to clarify whether a dynamic 
troponin elevation is associated with poor functional and cognitive outcome as well as higher mortality 
after stroke. 
 
Setting: 
The study is financed by the German Center for Cardiovascular Research (DZHK) and the German 
Center for Neurodegenerative Diseases (DZNE). About 15 stroke centers in Germany will participate as 
recruiting study sites. The majority of recruiting study sites are university hospitals with both a 
neurology and a cardiology department. The PRAISE study is an observational study. Therefore, 
treatment of patients included in the PRAISE study will be at the discretion of the local treating 
physicians.  
 
Hypotheses: 
The primary hypothesis states that a dynamic change of troponin values > 50% after 3 hours1 indicates 
acute coronary syndrome in patients with acute ischemic stroke. In patients with acute ischemic 
stroke, change of troponin values in serial measurements is helpful to identify patients with acute 
coronary syndrome.  
Endpoint: diagnosis of acute coronary syndrome as established by an independent endpoint 
adjudication committee. 
 
First secondary hypothesis:  
Ischemic stroke patients with a dynamic change of troponin values have poorer functional outcome 
than patients with stable troponin values after three and twelve months. 
Endpoint:  
Functional outcome will be measured using the modified Rankin Scale (mRS) 16 as well as the Lawton 
Instrumental Activities of Daily Life Scale (IADL)17 three and twelve months after the index event. 
 
Second secondary hypothesis:  
Ischemic stroke patients with a dynamic change of troponin values have poorer cognitive outcome 
than patients with stable troponin values three and twelve months after the index event. 
Endpoint:  

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               5 
 
Cognitive outcome will be evaluated using the Montreal Cognitive Assessment (MoCA)18 and the 
Telephone Interview for Cognitive Status (TICS)19  
 
Third secondary hypothesis:  
Ischemic stroke patients with a dynamic change of troponin values have an increased risk of recurrent 
cardiovascular events and mortality compared to patients with stable troponin values.  
Endpoint:  
Rates of recurrent ischemic strokes, TIA, myocardial infarction and mortality after three and twelve 
months. 
 
Study population: 
According to the sample size calculation, 251 stroke patients will be included prospectively. Both male 
and female patients will be included. Pregnant or breastfeeding patients will not be eligible for 
inclusion. The study will only recruit patients ≥ 18 years of age. 
 
Inclusion criteria: 
- age ≥ 18 years 
- written informed consent  
- diagnosis of ischemic stroke based on clinical symptoms and imaging (cranial CT or MRI) < 72 h after 
symptom onset 
- troponin elevation:  
a) either highly abnormal initial troponin levels (Elecsys-Assay hs-cTnT > 52ng/l, Architect-
Assay hs-cTnI > 52 ng/l20, Dimension Vista Assay hs-cTnI > 107 ng/l21)  
or 
b) dynamic troponin elevation with Δ change > 20% of the initial value after 3 hours and at 
least one value above the assay-specific upper reference limit according to ESC guidelines12  
- diagnosis of transient ischemic attack, if the initial focal neurological deficit was objectified by a 
neurologist during clinical examination and the patient has an ABCD2-Score22 ≥ 4 points 
- patient willing to participate in follow-up via telephone interview 
 
Exclusion criteria: 
- renal insufficiency (i.e. estimated glomerular filtration rate (eGFR) < 30 ml/min/1,73 m²)22  
- manifest hyperthyroidism 
- cerebral infarct > 100 ml on diffusion weighted imaging (DWI-MRI) or on cranial CT (if performed > 
24 hours after symptom onset) or ASPECTS-Score23 < 7 (if cranial CT was performed within 24 hours 
of symptom onset)  
- pregnancy or breast feeding 
- relative contraindications for coronary angiography (e.g. acute renal failure, acute bleeding, known 
allergy to contrast agent, manifest hyperthyroidism, respiratory failure, hemodynamic instability not 
explained by acute coronary syndrome)24 
- predmorbid Rankin score (mRS) > 3  
- life expectancy < 1 year 
- participation in an interventional study according to Medicinal Products Act (AMG) or Medical 
Devices Law (MPG) 
 
Stopping rules 
 
a) for the individual patient 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               6 
 
Every patient has the right to withdraw their consent to participate in the study at any time and 
without the need to state a reason for their withdrawal of consent. The patient may communicate 
their withdrawal of consent in oral or written form.   
If a study participant withdraws consent, any data that has been collected will be anonymized. In 
addition, every study participant has the right to demand that their personal data be deleted. 
By withdrawing consent from participation in the PRAISE study, the participant also withdraws consent 
from participation in the DZHK biobanking (see below). Withdrawal of consent has to be reported to 
the Trusted Third Party (THS) of the DZHK. The THS will ensure that all data are anonymized by 
eliminating the link between the participant9s pseudonym and their personal data. In addition, all 
collected biosamples will be destroyed.  
 
b) for the entire study 
The final decision for premature termination of the entire study lies with the Principal Investigators 
and the Steering Committee. The study9s Data Safety Monitoring Board (DSMB) may recommend the 
premature termination of the study due to safety concerns. The DSMB will report to the Steering 
Committee on the study9s safety after inclusion of 100 and 200 patients, respectively. All severe 
adverse events of special interest (SAESI, see below) will be collected and evaluated by a Critical Events 
Committee (CEC) and the results of the evaluation will be reported to the Data Safety Monitoring Board 
(DSMB). Possible reasons for premature termination of the entire study include 
- 
Unexpectedly high rate of SAESI 
- 
Unexpected SAESI that change benefit/risk assessment of the complete study 
- 
Low rate of recruitment 
 
c) for an individual study site 
Possible reasons for early termination of the study at an individual study site include  
- 
Repeated major protocol violations 
- 
Continuously low rate of recruitment (< 5 patients/year for two years in a row) 
The decision on early termination of the study at an individual study site is made by the principal 
investigators after consulting the Steering Committee. If an individual study site wishes to terminate 
their participation prematurely, they are required to notify the principal investigators in writing.  
 
Study procedures: 
Patients with acute ischemic stroke that undergo inpatient treatment at one of the PRAISE study sites 
may be included into the PRAISE study. Acute ischemic stroke will have to be diagnosed by an 
experienced neurologist at the recruiting study site. All patients will undergo cranial imaging (i.e. cCT 
or cMRI) as part of clinical routine before inclusion to rule out differential diagnoses to ischemic stroke. 
Patients will be eligible for inclusion within 72 hours after hospital admission. ECG, echocardiography 
and coronary angiography will have to be performed within 7 days after hospital admission.  
 
Patient history and clinical examination: 
Upon study inclusion (V1) the patient9s clinical history will be taken and a clinical examination will be 
performed. The data will be collected in accordance with the DZHK basic data set (DZHK-SOP-K-02)25. 
In addition, we will gather data on current medication, premorbid mRS, the National Institutes of 
Health Stroke Scale (NIHSS)26 on admission as well as the GRACE-Score. During the second study visit 
(V2, within 7 days after study inclusion), we will perform the NIHSS, mRS and perceived stress scale 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               7 
 
(PSS). In addition, we will collect data on the patient9s current medication. A 12-lead ECG will be taken 
at V1 and V2 according to DZHK-SOP-K-0327. 
 
Coronary angiography: 
All patients included in the study will undergo coronary angiography, which is the gold standard to 
diagnose a coronary culprit lesion. The timing of coronary angiography will be determined according 
to the ESC guideline recommendations on risk stratification28. Coronary angiography will be performed 
according to a SOP. Treating cardiologists may choose the cardiac catheter for coronary angiography. 
We will collect data on duration of the procedure, amount of contrast agent given, puncture site (radial 
vs. femoral), periprocedural anticoagulation, balloon dilatation and stent angioplasty. In addition, we 
will collect data on periprocedural complications, e.g. dissections, arrhythmias, thrombus formation, 
perforation, cardiac tamponade and type 4a myocardial infarction. For central reading in the core 
laboratory, imaging data will be uploaded via the imaging data management system (BDMS) of the 
DZHK. Coronary lesions will be evaluated regarding their localization and morphology according to the 
AHA classification.  
 
Echocardiography:  
Transthoracic echocardiography (TTE) will be performed by a cardiologist at the participating study site 
according to DZHK-SOP-K-0829. For central reading in the core laboratory, imaging data will be 
uploaded via the imaging data management system (BDMS) of the DZHK.  
 
Troponin: 
Acute ischemic stroke patients with elevation of troponin values according to the inclusion criteria (see 
above) will be eligible for inclusion into the PRAISE study. Troponin will be measured on admission and 
after three hours during clinical routine in all recruiting study sites. A dynamic elevation of troponin is 
defined as a 20% change of troponin values in serial measurement with at least one value elevated 
above the assay-specific upper reference limit. Since not all recruiting study sites will use the same 
assay for measuring troponin in clinical routine, troponin will also be measured at a central core 
laboratory located at the University Hospital Hamburg-Eppendorf (Prof. Blankenberg). At the core 
laboratory, high-sensitivity (hs)-Troponin-T will be measured using the Roche Elecsys-Assay and hs-
Troponin I will be measured using the Siemens Architect-Assay. 
 
12-lead ECGs, echocardiography and coronary angiography will be evaluated by independent and 
blinded core laboratories (Uni.-Prof. Dr. med. Burkhard Pieske at Charité Campus Virchow Klinikum for 
echocardiography, Uni.-Prof. Dr. med. Wilhelm Haverkamp at Charité Campus Virchow Klinikum for 
ECG und Univ.-Prof. Dr. Ulf Landmesser at Charité Campus Benjamin Franklin for coronary 
angiography).  
The diagnosis of „acute coronary syndrome= is the study9s primary endpoint and will be established by 
an independent endpoint adjudication committee according to the ESC guidelines. The endpoint 
adjudication committee will take the results of coronary angiography, ECG and echocardiography as 
well as clinical symptoms into account. The endpoint adjudication committee will be blinded to 
patients9 troponin levels. 
 
DZHK Biobanking: 
All patients included in the PRAISE study will be offered optional participation in the DZHK biobanking. 
If the patient agrees to participate in the DZHK biobanking, blood and urine samples will be taken 
during V2. The documentation process depends on whether the recruiting study site is also a DZHK 
site. The exact procedure is described in DZHK-SOP-B-01 and DZHK-SOP-B-02. Biosamples will be 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               8 
 
stored at the participating study sites at -80°C. If a participant withdraws consent to participate in the 
DZHK biobanking, all collected biosamples will be destroyed. A withdrawal of consent to participate in 
the PRAISE study automatically includes withdrawal of consent to participate in the DZHK biobanking.  
 
Cognition: 
Cognitive performance will be assessed during V1 and V2 using the Montreal Cognitive Assessment 
(MoCA). In addition, cognitive performance will be assessed during follow-up visits using the 
Telephone Interview for Cognitive Status (TICS). At V1 the Informant Questionnaire on Cognitive 
Decline in the Elderly (IQCODE)30 will be performed to assess cognitive decline prior to the index stroke. 
In order to differentiate between cognitive impairment and delirium, we will use the Delirium Rating 
Scale (DRS)31 at V1.   
 
Functional Outcome: 
Functional outcome will be assessed using the modified Rankin Scale (mRS) and the Lawton 
Instrumental Activites of Daily Living Scale (IADL). mRS will be assessed at V1, V2 and both telephone 
follow-up visits (see below). IADL will be assessed during telephone follow-up visits. The secondary 
endpoints recurrent myocardial infarction, recurrent cerebral ischemia (ischemic stroke or TIA) and 
mortality will be assessed at V2 as well as both telephone follow-up visits.  
 
Follow-up: 
Follow-up will be performed three and twelve months (± 14 days) after the index stroke in form of 
telephone interviews. During the telephone interviews, cognitive outcome and functional outcome 
will be assessed as described above. In addition, patients will be questioned on recurrent 
cardiovascular events (i.e. myocardial infarction, stroke and TIA). Data on mortality will be acquired 
from local registration offices.  
 
Data management: 
Data for the PRAISE study will be collected at each individual study site using an eCRF (electronic case 
report form). The PRAISE study will use the scientific infrastructure of the DZHK for data collection and 
storage. Data will be collected and stores according to the requirements of the data protection policy 
of the DZHK32 as well as Guidelines for Good Clinical Practice (GCP). Data will be stored using the 
webbased tool <secuTrial=, which conforms with all regulatory standards of the FDA32. In case of 
participation in the DZHK biobanking, all biosamples will be stored locally in the recruiting study sites 
(see above).  
 
The DZHK has a central data management (ZDM), which consists of three institutions 
o Trusted third party (THS) at the Institute of Community Medicine, Greifswald 
o Data repository (DH) at the Institute of Medical Informatics, Göttingen 
o IT-administration at the DZHK main office  
 
Medical data that are entered into the eCRF will be stored at the study database of the DH. The 
patients8 personal data will be stored on the servers of the THS. Thus, the patients8 personal data and 
the patients8 medical data will be stored on separate servers provided by different organizations. Only 
the individual study sites will have access to both the patients9 personal and medical data. 
 
The THS will provide the eCRF for collection of patients8 personal data via secuTrial. Thus, data will be 
stored directly on the servers of the THS. The signed informed consent (IC) form will be scanned and 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               9 
 
sent to the THS electronically. Informed consent will also be documented electronically via a separate 
eCRF. The THS will subsequently generate the patient9s pseudonym, which will be used to enter the 
patient9s medical data.  The patient9s pseudonym will be available to the local staff at the study site. 
The DH will provide the eCRF for the collection of medical data. For central assessment of coronary 
angiography, transthoracic echocardiography (TTE) and ECG, imaging data will be uploaded using the 
image data management system (BDMS) of the DZHK. The respective core laboratories will have 
separate eCRFs in secuTrial to enter the results of imaging assessment.  
 
All source documents are stored in the Investigator Site File/Study Patient File. Source documents are 
stored locally at the recruiting study sites for 10 years.  
 
Study variables: 
Identifying data: 
Name, patient number, sex, date of birth, age, address, telephone number 
 
General examination: 
DZHK basic data set 
Current medication 
NIHSS (0-42) 
mRS (0-6) 
 
laboratory diagnostics: 
troponin value at admission (in ng/l) 
troponin value after three hours (in ng/l) 
clinical chemistry 
DZHK-Biobanking (24 ml) (optional) 
 
Study-specific examinations: 
IADL (0-8) 
MoCA (0-30) 
TICS 
IQCODE 
GRACE-Score 
Beck Depression Inventory (BDI) (0-63)33 
DRS (0-39) 
Perceived Stress Scale (0-40) 
12-lead ECG (ACS-typical changes) 
Transthoracic echocardiography (regional wall motion abnormalities, left-ventricular ejection fraction) 
Coronary angiography (presence of coronary culprit lesion)  
 
Communication of test results 
If echocardiography or coronary angiography yield pathological findings, any decision on further 
diagnostic or therapeutic measures is at the discretion of the treating physicians at the study sites. 
Individual results of central imaging assessment in core laboratories will not be communicated with 
the participating sites or with patients.  
 
 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               10 
 
 
 
Screening (V1) 
Study-specific 
examinations (V2) 
Follow-up 1 
Follow-up 2 
 
< 
72 
h 
after 
admission 
< day 7 (+/- 1 day) 
3 months (+/- 
7 days) 
12 months (+/- 7 
days) 
Study inclusion 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Written informed consent 
X 
 
 
 
General examination 
 
 
 
 
DZHK basic data set 
X 
 
 
 
Premorbid mRS 
X 
 
 
 
Current medication 
X 
X 
 
 
NIHSS 
X 
X 
 
 
mRS 
X 
X 
X 
X 
Cognitive tests 
 
 
 
 
TICS 
 
 
X 
X 
MoCA 
X (Version A) 
X (Version B) 
 
 
IQCODE 
 
X 
 
 
BDI 
 
 
X 
X 
DRS 
X 
 
 
 
perceived stress scale 
 
X 
 
 
Gender term (Sub-study) 
 
X 
 
 
Laboratory diagnostics 
 
 
 
 
Troponin (0 und 3 h) 
X 
 
 
 
Clinical chemistry 
X 
 
 
 
DZHK-Biobanking (optional) 
 
X 
 
 
Study-specific examinations 
 
 
 
 
GRACE-Score 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
ECG 
X 
X 
 
 
Echocardiography (TTE) 
 
X 
 
 
Coronary angiography 
 
X 
 
 
endpoints 
 
 
 
 
Acute coronary syndrome (ACS) 
 
X 
 
 
Recurrent cerebral ischemia, 
myocardial infarction, mortality 
 
X 
X 
X 
Table 1: PRAISE study procedures 
 
Statistical analysis: 
Sample size calculation: 
The sample size calculation of the PRAISE study is based on data from the TRELAS study (Troponin 
elevation in acute stroke)9. In the TRELAS study, 7/29 (24%) of ischemic stroke patients with troponin 
elevation had a coronary culprit lesion and 11/29 (38%) of patients had dynamic troponin elevation 
(i.e. Δ change > 50%). Of 11 patients with dynamic troponin elevation, 6 patients (54%) had a coronary 
culprit lesion. In patients without dynamic troponin elevation, only one patient (1/18=6%) had a 
coronary culprit lesion. Thus, the odds ratio of a dynamic troponin elevation for presence of a coronary 
culprit lesion was at 20.4. Due to the small sample size of the TRELAS study, we used the lower limit of 
the 80% confidence interval of the odds ratio (~4) to calculate the sample size for the PRAISE study. 
We assumed that the proportion of stroke patients with dynamic troponin elevation will be similar to 
the TRELAS study. Thus, 203 patients will have to be included to achieve a statistically significant result 
with a power of 80% (alpha=0.05). Since the TRELAS study only recruited patients with an initial hs-
troponin T value > 50 ng/l (Roche Elecsys Assay), the proportion of patients with dynamic troponin 
elevation will likely be even higher in PRAISE. In order to compensate for cases of withdrawal of 
consent we plan to include 251 patients. The primary hypothesis will be tested using an intention-to-
diagnose analysis by calculation of the odds ratio of acute coronary syndrome in patients with dynamic 
vs. stable troponin elevation. Secondary endpoints will be analyzed using the same statistical method. 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               11 
 
In order to assess other predictors of acute coronary syndrome we will use the Chi-Square-test for 
dichotomous variables and the Wilcoxon-Test for continuous variables.  
In addition, we will perform univariable analyses and multivariable logistic regression analyses to 
calculate unadjusted and adjusted odds ratios for acute coronary syndrome. We will take a number of 
baseline regressors into account including age, sex, GRACE-Score, history of coronary heart disease, 
atrial fibrillation, heart failure, wall motion abnormalities on echocardiography and ACS-typical 
changes on ECG.   
In an exploratory analysis, we will calculate an optimized multivariable logistic regression model using 
backward selection. In addition, we plan to calculate the best cut-off of troponin levels to predict acute 
coronary syndrome using the maximum area under the receiver operating characteristic (ROC) curve.   
Subgroup analyses will be defined in the statistical analysis plan before the first endpoint analysis is 
performed.  
 
Interim analyses 
In order to assess safety of the study, we will perform an interim analysis of the occurrence of serious 
adverse events of special interest (SAESI, see below) after inclusion of 100 and 200 patients, 
respectively. This analysis will be used by the DSMB to consult the Steering Committee concerning the 
continuation or premature termination of the study due to safety concerns.  
 
Methods against bias 
PRAISE is a multicenter observational study. Recruiting sites are stroke centers in Germany. The 
diagnosis of <acute ischemic stroke= will be established by experienced neurologists. ECG, 
echocardiography and coronary angiography will be performed by experienced cardiologists according 
to SOPs. All study examinations will be re-assessed by blinded core laboratories (see above). Since 
troponin will be measured by the recruiting study sites before study inclusion using different assays, 
troponin will also be re-measured at a core laboratory (Prof. Blankenberg, UKE Hamburg) using the 
same biosamples. The primary endpoint will be adjudicated by an independent endpoint adjudication 
committee, which will be blinded to patients9 troponin levels. The assessment of functional and 
cognitive outcome will be performed using standardized scores (see above).    
The primary hypothesis that has been described in this protocol will be tested in an intention-to-
diagnose analysis in order to prevent possible selection bias. A per-protocol-analysis is planned as a 
secondary analysis.  
 
 
 
 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               12 
 
Study timeline: 
Year one (Q3 2018-Q2 
2019) 
Year two (Q3 2019-Q2 
2020) 
Year three (Q3 2020-
Q2 2021) 
Year four (Q3 2021- 
Q2 2022) 
 
 
 
 
Fig. 1: study timeline 
 
Ethical considerations: 
The study will be conducted according to the Guidelines for Good Clinical Practice (ICH Harmonized 
Tripartite Guidelines for Good Clinical Practice 1996 Directive 91/507/EEC; D.M. 15.7.1997)34 and the 
Declaration of Helsinki35. By signing the study contract, the study sites agree to conduct the study 
according to the study protocol. All examinations during the course of the study will be performed 
according to current guidelines of the European Society of Cardiology (ESC). Patients unable to provide 
informed consent may not be included in the study. For inclusion into the study, both the study 
physician and the patient have to sign the written informed consent form.  
The study was approved by the Ethics Committee of Charité-Universitätsmedizin Berlin on March 29 
2018. 
 
Data protection: 
The data will be collected and stored using the DZHK scientific infrastructure (see above). Therefore, 
our data protection policy builds on the DZHK data protection policy32. We will use the webbased tool 
secuTrial for data collection.  
The servers of the THS and DH are protected by multi-stage firewall systems. The communication 
between server and clients is always encrypted. Communication with the THS is only possible with the 
client9s pre-registered IP address and port. In addition, it is possible to define certain roles within 
secuTrial so that the access to the data may be adapted to different groups of study personnel. Each 
role is equipped with its own set of rights to access, enter and modify data.   
During the process of data collection, data editing and query management, secuTrial creates an audit 
trail for every data point. The audit trail provides an overview of all changes that have been made and 
saved in an eCRF. Management of queries will also be realized via secuTrial and will only be accessible 
for registered users.  
 
Preparation 
Recruitment (24 months) 
Follow-up 1 (after 3 months) 
Follow-up 2 (after 12 months) 
Data clearing 
Data analysis 
Publications 
First milestone:         
n = 100 recruited 
Second milestone:      
n = 200 recruited 
Third milestone: 
final analysis of 
primary endpoint 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               13 
 
Data transfer: 
Data collected during the course of the PRAISE study will be stored indefinitely within the DZHK 
infrastructure using a pseudonym. By providing informed consent, study participants will grant the 
DZHK unlimited right to use the stored data. In addition, study participants will agree to transfer the 
ownership right to their biosamples that have been collected during the DZHK biobanking to the DZHK. 
If external researchers wish to use data or biosamples collected in DZHK-funded studies, they may 
write a scientific project proposal to the DZHK. The DZHK may then grant the researchers non-
exclusive, non-transferrable rights to use data for the purpose of the project for a limited time. Any 
research proposal sent to the DZHK will be evaluated by the DZHK Use and Access committee according 
to the DZHK use and access policy36. External researchers agree via contract that they will not try to re-
identify patients, to copy data or biosamples or to forward them to any third party. After transfer of 
the data, the external researchers are required to delete the data within 5 years after the end of the 
contract period and to inform the DZHK accordingly.  
The transfer of data to external researchers is only possible after a period of protection, which ends 
two years after the study has been completed. Within the period of protection, only the study9s 
principal investigators have an unlimited right to use the data collected during the study. 
 
Rights to publications: 
The principal investigators of the PRAISE study plan to publish the main results of study together with 
the local investigators of all recruiting study sites. Before the publication of the study9s main results, 
the investigators at recruiting study sites agree not to publish any of the data that have been collected 
at their respective study sites. If the principal investigators or financers of the study (i.e. the DZHK or 
DZNE) should intend to apply for intellectual property rights, the principal investigators will have the 
right to delay the publication of the study9s main results. This is also applicable if the study should be 
terminated prematurely. The principal investigators will decide on the content of the publication. The 
investigators at recruiting study sites agree not to publish any confidential information. In any case, 
publications planned by investigators at recruiting study sites will have to be coordinated and agreed 
upon with the principal investigators (who may not deny the right to publication without reasonable 
arguments).    
 
Patient treatment: 
If the diagnosis of acute coronary syndrome cannot be confirmed, the choice of secondary stroke 
prevention will be at the discretion of the treating physicians. If a diagnosis of acute coronary 
syndrome is confirmed, the individual case will be discussed between the neurologists and 
cardiologists at the recruiting study sites in order to decide on further treatment. Treating physicians 
are encouraged to consult the ESC guidelines for appropriate treatment decisions. However, since 
PRAISE is an observational study, all treatment decisions lie with the treating physicians.  
 
Risks for study participants: 
Coronary angiography will only be performed in a study patient after thorough information on 
potential risks and benefits and if the patient provides informed consent. Coronary angiography will 
be performed according to ESC guideline recommendations. In order to avoid risks related to the 
application of contrast agent, patients with renal insufficiency (eGFR < 30 ml/min), manifest 
hyperthyroidism and allergy to contrast agent may not be included. In addition, patients who are 
hemodynamically unstable with their condition not being sufficiently explainable by acute coronary 
syndrome, are not eligible for inclusion. In order to reduce the risk for intracerebral hemorrhage 
related to periprocedural antithrombotic treatment, patients with very large ischemic lesions may not 
be included (see exclusion criteria).  

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               14 
 
 
Quality control: 
The THS and DH of the DZHK offer web-based seminars to any initiator of a DZHK study. During the 
course of the webinar, the technical processes are explained and issues may be solved before study 
initiation. After initiation of several study sites there will be a quality training to educate study 
personnel, e.g. on the correct data collection process. Investigators at recruiting study sites will ensure 
that their staff is trained adequately.   
Before the start of recruitment at any study site, there will be a site initiation visit by the study 
coordinators. During the recruitment period, we plan two monitoring visits at each study sites. During 
the course of monitoring visits, all informed consent forms will be checked. In addition, all further 
source data will be checked in at least 10% of patients per study site. Before recruitment for the PRAISE 
study commences, study-specific quality control measures will be determined in a monitoring manual. 
In addition to in-person monitoring, all data entered into the study database will be subjected to a 
review process. After the data for a study visit has been entered into the eCRFs, the investigator at the 
recruiting study site will have to assign the <Review A= status to the respective eCRFs. The <Review A< 
status signifies that the data entry is complete so that quality control measures including remote 
monitoring can be performed. Quality control measures include remote monitoring by a study nurse 
from the study9s main office as well as automated quality control by the DH. After completion of quality 
control measures including query management, the study9s main office will assign the <Review B= 
status to the eCRFs. After the „Review B< status has been set, data cannot be entered, modified or 
deleted anymore. Only data that have been assigned the <Review B= status may be forwarded to 
external researches according to the DZHK Use and Access Policy. 
 
Safety, SAESI: 
A „Serious Adverse Event of special interest< (SAESI) is an event, which may cause prolongation of the 
in-hospital treatment, renewed admission to hospital, functional impairment or death of the study 
participant. SAESI are defined to include potential complications of coronary angiography.  
In the PRAISE study, the following events are defined as SAESI: 
• 
Ischemic stroke37 
• 
Transient ischemic attack (defined as focal neurological deficit lasting for < 24 hours) 
• 
Intracerebral hemorrhage38,39 
• 
Subarachnoid hemorrhage39 
• 
Severe hemorrhage (defined as hemorrhage type 3-5 according to the BARC classification)40 
• 
Type 4 myocardial infarction1 
• 
Peripheral arterial occlusion 
• 
Anaphylactic shock41 
• 
Renewed coronary revascularization during the in-hospital stay 
• 
death 
All SAESI will be documented by the study personnel on the appropriate eCRF in secuTrial within three 
work days. The study coordinators will be informed automatically if a new SAESI is reported. Study 
sites are required to evaluate all SAESI regarding their severity and potential causal relationship with 
coronary angiography.  
All reported SAESI will be evaluated by the Critical Events Committee (CEC) regarding their 
classification, relevance and causal relationship with coronary angiography. All CEC meetings have to 
be attended by at least one neurologist and one cardiologist. The adjudicating members of the CEC 
may not be involved in the treatment of study patients whom they are evaluating. The adjudication 
will be carried by vote of majority. The adjudication of the CEC will be documented on a separate eCRF 

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               15 
 
in secuTrial. The DSMB is required to write a report on their assessment of the study9s safety after 
inclusion of 100 and 200 patients, respectively. The DSMB will consult the Steering Committee 
regarding its recommendation of study continuation or premature termination due to safety concerns.  
 
Financial compensation: 
Study participants will not receive financial compensation. 
 
Insurance: 
Study participants from all study sites will be insured via study insurance provided by Newline 
Insurance Company Limited. 
 
Berlin, 19.06.2018 
 
 
(Prof. Dr. med. Matthias Endres) 
Principal Investigator 
 
 
 
Dr. Matthias 
Endres
Digital unterschrieben von 
Dr. Matthias Endres 
Datum: 2024.10.24 16:46:27 
+02'00'

 
 
 
 
PRAISE-Studienprotokoll_V1.1_19.06.2018                                               16 
 
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