Efficacy and Safety of Intravenous Thrombolysis in Branch Atheromatous Disease - a Retrospective Data Analysis
Conditions: Stroke, Thrombolysis, DAPT(Dual Antiplatelet Therapy), SAPT(Single Antiplatelet Therapy), Acute Ischemic Stroke
Sponsor: Sigmund Freud PrivatUniversitat

Study Protocol 
 
Efficacy and Safety of Intravenous Thrombolysis 
in Branch Atheromatous Disease  
 
International multicenter observational study 
 
Version 1.2/ 22.04.2025 
 
 
Principal Investigators: 
Univ.-Prof. Dr. Marek Sykora, PhD, MSc 
Department of Neurology, St. John's Hospital, Vienna, Austria 
Sigmund Freud University Vienna, Austria. 
 
 
Co-Principal Investigators: 
Prof. Dr. Sven Poli  
Prof. Dr. Jan C. Purrucker 
Prof. Dr. Christian Nolte  
Prof. Dr. Patrik Michel 
Prof. Dr. S. Greisseneger 
 
 

 
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Table of content 
 
TABLE OF CONTENT ......................................................................................................................................... 2 
COLLABORATING INSTITUTIONS ................................................................................................................ 3 
LIST OF ABBREVIATIONS ................................................................................................................................ 4 
BACKGROUND ..................................................................................................................................................... 5 
AIMS ........................................................................................................................................................................ 5 
METHODS .............................................................................................................................................................. 5 
STUDY POPULATION ............................................................................................................................................. 6 
Inclusion criteria.............................................................................................................................................. 6 
Exclusion criteria ............................................................................................................................................. 6 
ENDPOINTS............................................................................................................................................................ 6 
INFORMED CONSENT ............................................................................................................................................. 6 
STUDY SITE ........................................................................................................................................................... 7 
STUDY DESIGN ...................................................................................................................................................... 7 
SAMPLE SIZE ......................................................................................................................................................... 7 
COLLECTED DATA ................................................................................................................................................ 8 
DATA MANAGEMENT ............................................................................................................................................ 9 
STATISTICS ............................................................................................................................................................ 9 
ETHICAL CONSIDERATIONS ................................................................................................................................. 10 
TIME FRAME ........................................................................................................................................................ 10 
REFERENCES ..................................................................................................................................................... 10 
 

 
3 
Collaborating Institutions 
 
Investigator 
Institution 
Prof. Dr. Sven Poli 
Department of Neurology & Stroke, University 
of Tübingen, Tübingen, Germany. 
Prof. Dr. Jan C. Purrucker 
Department of Neurology, Heidelberg University 
Hospital, Heidelberg, Germany. 
Prof. Dr. Christian Nolte 
Department of Neurology, Berlin Institute of 
Health, 
Charité-Universitätsmedizin 
Berlin, 
Berlin, Germany. 
Prof. Dr. Patrik Michel 
Prof. Dr. Davide Strambo 
Stroke Center, Neurology Service, Department of 
Clinical Neurosciences, Lausanne University 
Hospital and University of Lausanne, Lausanne, 
Switzerland. 
Prof. Dr. Stefan Greisenegger 
Department of Neurology, Medical University 
Vienna, Vienna, Austria 
 
 
 

 
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List of abbreviations 
 
BAD 
branch atheromatous disease 
LSA 
lenticulostriate artery 
PPA 
paramedian pontine artery 
ACHA 
anterior choroidal artery 
µm 
micrometer 
END 
early neurological deterioration 
SAPT 
single antiplatelet therapy 
DAPT 
dual antiplatelet therapy 
DWI 
diffusion-weighted 
MRI 
magnetic resonance imaging 
RSSI 
recent small subcortical infarction  
BA 
basilar artery 
MCA 
middle cerebral artery 
ICA 
internal carotid artery 
mRS 
modified Rankin scale 
NIHSS 
National Institutes of Health Stroke Scale 
IVT 
intravenous thrombolysis 
LMWH 
low-molecular-weight heparin 
mmHg 
millimeter of mercury 
INR 
international normalised ratio 
 

 
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Background 
Intracranial branch atheromatous disease (BAD) describes an occlusion of deep penetrating intracranial 
arteries, leading to subcortical infarction (1). Perforating arteries include the lenticulostriate artery 
(LSA), paramedian pontine artery (PPA), anterior choroidal artery (ACHA), thalamoperforating artery, 
and Heubner’s artery (1-3). This study focuses on BAD affecting the ACHA, LSA, and PPA. 
In contrast to lacunar ischemia, which is caused by hypertensive lipohyalinotic degeneration of the distal 
segment of a perforating artery with a diameter ≤200 µm, BAD involves larger vessels (700-800 µm) 
affected by atherosclerosis of the parent artery (4). BAD has not been classified as a major cause of 
cerebral infarction by the National Institute of Neurological Disorders and Stroke (NINDS) or the Trial 
of Org 10172 in Acute Stroke Treatment (TOAST), which has contributed to a rather scarce data 
regarding clinical trajectories of this particular stroke etiology (5, 6). According to TOAST criteria, 
BAD-related strokes are often categorized under small vessel occlusion or classified as an undetermined 
cause (4, 6, 7). Due to their vessel size, high pressure and flow, these arteries are more susceptible to 
endothelial damage and atherosclerosis, leading to fluctuating symptoms (8, 9). At admission, BAD 
often presents similarly to lacunar ischemia (8). But in comparison, a main clinical characteristic of 
BAD is the frequent occurrence of early neurological deterioration (END), often manifesting as 
progressive motor deficits, which contribute to poorer outcomes and increased disability (2, 10, 11). 
Consequently, BAD has been recognized as a major vascular mechanism of progressive motor deficits 
in penetrating artery infarcts (11). Because of its unique pathophysiology and clinical progression, 
finding effective treatment strategies remains difficult. Intravenous thrombolysis (IVT) appears to be 
less effective for BAD compared to other etiologies of acute ischemic stroke (12). Previous studies have 
explored various treatment strategies, including dual antiplatelet therapy, tirofiban, and anticoagulation 
therapy, but results have been inconsistent (9, 13-15).  This study will assess the efficacy and safety of 
IVT versus antiplatelet therapy in BAD-related stroke. Furthermore, we will examine the impact of 
blood pressure on END and functional outcomes. 
Aims 
The primary aim of this study is to assess the efficacy and safety of IVT compared to single (SAPT) or 
dual antiplatelet therapy (DAPT) in patients with BAD-related stroke. Secondary aim is to explore the 
impact of blood pressure fluctuations on END and functional outcomes and its potential interactions 
with acute therapies.  
Methods 
This study is an international multicenter observational study recruiting patients with BAD-related 
stroke in the acute phase on the stroke unit up to 24 hours before admission. As of March 15, 2025, this 
study has invited and confirmed 5 collaborating institutions, led by Department of Neurology, St. John’s 

 
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Hospital and SFU Med Vienna, Austria 
 
Study Population 
All patients with a BAD-related stroke, aged over 18 years, with symptom onset no more than 24 hours 
before admission, who were treated in one of the stroke units of the participating institutions between 
2010 and 2025, will be included based on the following inclusion criteria. All enrolled patients must 
have undergone a cerebral MRI for inclusion. 
Inclusion criteria 
1. DWI lesion: single isolated deep subcortical stroke AND 
2. The affected vessel involves the LSA, PPA, or ACHA, and the infarct lesion on DWI conforms 
to one of the following characteristics (A, B, OR C): 
 
A. LSA: “Comma-like” infarct lesions with “fan-shaped” extension from bottom to top in the 
coronary position OR ≥ 3 layers (layer thickness 5 mm) on axial DWI. 
B. PPA: Infarct lesion extending from the deep pons to the ventral pons on axial DWI. 
C. ACHA: Infarct within the anterior choroidal artery territory. 
Exclusion criteria 
1. Typical recent small subcortical infarction (RSSI) (oval, <20mm in all axes). 
2. ≥ 50% stenosis on the parent artery (i.e., BA, MCA, or ICA) 
3. Stroke due to other clearly identified causes or possible cardioembolic etiology. 
  
Endpoints 
The primary endpoints of this study include: 
1. Modified Rankin Scale (mRS) score at three months, with a favorable outcome defined as mRS 
0-1 at three months. 
2. Early neurological deterioration (END), defined as a worsening of the NIHSS score by ≥4 points 
within 24-48 hours after symptom onset. 
3. Occurrence of symptomatic intracerebral hemorrhage. 
 
Interventions  
Intravenous thrombolysis (IVT), single antiplatelet therapy (SAPT), dual antiplatelet therapy (DAPT), 
blood pressure treatment. All intervention s are indicated clinically based on local protocols and 
international guidelines and their indication is not related to this study 

 
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Hypothesis 
H1. Patients with BAD related stroke treated using IVT will achieve better functional outcome as 
compared to those treated with SAPT.  
 
H2. Patients with BAD related stroke treated using IVT will not achieve better functional outcome as 
compared to those treated with DAPT.  
 
H3. Patients with BAD-related stroke experiencing blood pressure drop >=30 mmHg in the first 24 
hours after admission will experience worse functional outcome as compared to those without blood 
pressure drop. Interaction with IVT will be significant.   
 
Informed consent 
Due to the retrospective nature of the study and the use of anonymized data, obtaining patient 
informed consent is not necessary. 
 
Study sites 
Institutions participating in this study, with a full list of institutions provided under collaborating 
institutions. The leading institution is the Department of Neurology, St. John’s Hospital, Vienna, Austria 
 
Study design 
The study will be conducted as an international multicenter retrospective observational study according 
to the STROBE guideline (16).  
 
Sample size 
The estimated sample size is approximately 200-400 patients. As additional institutions are expected to 
join the study, the total sample size may further increase. 

 
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Collected Data 
The collected data are listed in  
 
Table 1. 
 
 
Table 1: collected data 
Category 
 
Variables 
Baseline 
characteristics 
 
Age, Gender 
Medical history 
 
Arterial hypertension (yes/no), Diabetes mellitus 
(yes/no), Atrial fibrillation (yes/no), Myocardial 
infarction (yes/no), Hypercholesterolemia (yes/no), 
Peripheral artery disease (yes/no), Smoking (yes/no), 
Renal insufficiency (yes/no) 
Pre-Stroke Condition 
 
mRS before stroke 
Current Stroke 
 
 
 
Time 
information 
Year of stroke, Onset-to-Door Time (min), Door-to-
Needle Time (min) 
 
Clinical 
Information 
NIHSS on admission, Onset type (known, wake-up, 
unknown), NIHSS after 24 to 48h and/or NIHSS at 
stroke unit discharge, mRS at stroke unit discharge, 
mRS after 3 months, END (yes/no) 
 
Localization 
Radiological classification into LSA, PPA, or ACHA 
based on inclusion criteria, Localization 
(supratentorial - right/left/bilateral; brainstem; other), 
Internal capsule involvement (yes/no) 
 
Medication 
before Stroke 
Antiplatelet therapy (none, mono, dual), Vitamin K 
antagonist (yes/no), INR at admission, Apixaban 

 
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(yes/no), Dabigatran (yes/no), Edoxaban (yes/no), 
Rivaroxaban (yes/no) 
 
Therapy after 
admission 
IVT (yes/no), Alteplase (yes/no), Tenecteplase 
(yes/no), Antiplatelet therapy (none, mono, dual), 
Vitamin K antagonist (yes/no), Apixaban (yes/no), 
Dabigatran (yes/no), Edoxaban (yes/no), 
Rivaroxaban (yes/no), Full-dose LMWH 
anticoagulation (yes/no) 
 
Blood Pressure 
after 
admission 
Systolic blood pressure at admission (mmHg), 
Diastolic blood pressure at admission (mmHg), Need 
for antihypertensive therapy before IVT or DAPT 
(yes/no), Minimum systolic blood pressure within the 
first 24h on the stroke unit (mmHg), Minimum 
diastolic blood pressure within the first 24h on the 
stroke unit (mmHg), Blood pressure decrease ≥30 
mmHg within 24h (yes/no) 
 
 
Data management 
Collected data will be entered into an electronic database at the primary study site. All data will be fully 
anonymized and only shared in this form with researchers. Therefore, a data monitoring committee will 
not be required. All datasets will be exclusively used for this study, and no third party will be granted 
access at any time. 
Statistics 
The statistical analysis will be conducted using SPSS version 29.0.1.0 (IBM Corp., Armonk, NY, USA) 
and R version 4.4.2 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables 
will be presented as mean ± standard deviation (SD) or median with interquartile range (IQR), depending 
on their distribution. Categorical variables will be expressed as frequencies (n) and percentages (%). 
This includes variables such as baseline characteristics, medical history, and treatment modalities. For 
the analysis of statistical significance in outcome measures, Pearson’s χ² test or Fisher’s exact test will 
be applied for categorical data, while Wilcoxon rank-sum tests or t-tests will be used for continuous 
variables, as appropriate. Statistical uncertainty will be reported using 95% confidence intervals (CI). 
To evaluate the association between three-month mRS and clinical or therapeutic predictors, IPTW and  
Poisson regression models will be utilized (17). The results of the Poisson regression analysis will be 
reported as adjusted relative risks (RR) with corresponding 95% CI. A favorable functional outcome is 

 
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defined as mRS ≤1 at three months post-stroke. Statistical significance will be set at p<0.05. 
 
Ethical considerations 
This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice 
guidelines throughout the whole research process. Approval from the ethics committee will be obtained 
prior to data collection. As this is a retrospective, non-interventional study, there is no additional 
physical risk for patients. Data collection is exclusively based on previously recorded medical records. 
The primary ethical concern in this study relates to data transfer between institutions. To minimize this 
risk, only fully anonymized data will be shared with researchers. All collected data will be used solely 
for scientific research purposes, and no personal information will be disclosed or made accessible to 
third parties. 
 
Time frame 
The study is projected to start after approval is granted by the ethics committee of SFU Med (submitted).  
 
 
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