Efficacy and Safety of Intravenous Thrombolysis in Branch Atheromatous Disease

Official title

Efficacy and Safety of Intravenous Thrombolysis in Branch Atheromatous Disease - a Retrospective Data Analysis

Overview

Rationale and Relevance: Branch Atheromatous Disease (BAD) describes an atherosclerotic occlusion of one of the deep penetrating cerebral arteries, including the lenticulostriate artery (LSA), paramedian pontine artery (PPA), and anterior choroidal artery (ACHA). BAD is frequently associated with early neurological deterioration (END), particularly progressive motor deficits that contribute to increased disability. Despite its clinical relevance, BAD remains underrepresented in major radiomorphological classification systems such as TOAST, which has led to limited evidence and unclear treatment strategies. Previous studies suggest that the efficacy of intravenous thrombolysis (IVT) may be reduced in BAD compared to other stroke etiologies. Objectives: The primary objective of this study is to evaluate the efficacy and safety of IVT compared with single antiplatelet therapy (SAPT) and dual antiplatelet therapy (DAPT) in patients with BAD-related stroke. A secondary objective is to examine the impact of acute-phase blood pressure fluctuations on END and functional neurological outcomes. Design and Methods: This international multicenter study will be conducted retrospectively according to the STROBE guidelines. Eligible patients include those with BAD-related stroke treated at one of the participating centers between 2010 and 2025. Inclusion criteria comprise characteristic diffusion-weighted MRI patterns in predefined vascular territories (LSA, PPA, ACHA) and a symptom onset ≤24 hours before admission. Patients with typical lacunar infarcts or with other identified stroke etiologies will be excluded. Endpoints: Primary endpoints include functional outcome at three months, defined as a favorable outcome with a modified Rankin Scale score of 0-1; occurrence of END, defined as a ≥4-point worsening on the NIHSS within 24-48 hours; and symptomatic intracerebral hemorrhage. Collected data include clinical, imaging, and therapeutic variables, as well as blood pressure trajectories and pre-stroke treatments (as detailed in the study protocol). Statistical Analysis: Analyses will be performed using SPSS and R. Descriptive statistics, univariate analyses, and multivariable models (IPTW and Poisson regression) will be applied. Results will be reported as adjusted relative risks with 95% confidence intervals. Significance: This study will provide the first comprehensive evaluation of IVT versus SAPT/DAPT in BAD-related stroke, and will investigate the clinical impact of blood pressure changes in this specific stroke subtype. The findings aim to support evidence-based treatment recommendations for a currently underrecognized and poorly understood stroke etiology.

Detailed description

Intracranial branch atheromatous disease (BAD )describes an occlusion of deep penetrating intracranial arteries, leading to subcortical infarction. These perforators include the lenticulostriate arteries (LSA), paramedian pontine arteries (PPA), anterior choroidal artery (ACHA), thalamoperforating arteries, and Heubner's artery. This study specifically focuses on BAD affecting the LSA, PPA, and ACHA territories.

Unlike classical lacunar infarction, which is typically attributed to lipohyalinotic degeneration or fibrinoid necrosis of small distal perforators (\<200 µm), BAD involves more proximal and larger perforating arteries (approximately 700-800 µm in diameter). The underlying pathophysiology is thought to be predominantly atherosclerotic plaque involvement at or near the origin of the perforating artery from a parent vessel, resulting in progressive luminal narrowing, branch occlusion, or flow impairment. This distinguishes BAD from traditional small vessel disease and places it within a spectrum of intracranial atherosclerotic disease.

Despite its distinct vascular mechanism, BAD is not formally classified as a separate etiological subtype in major stroke classification systems such as TOAST or NINDS criteria. As a result, cases are often categorized under "small vessel occlusion" or "stroke of undetermined etiology," contributing to under-recognition and limited systematic evidence regarding optimal management strategies.

Clinically, BAD may initially present similarly to lacunar stroke syndromes, particularly pure motor or sensorimotor deficits. However, a main feature is early neurological deterioration (END), typically occurring within the first 24-48 hours after onset. END is characterized by stepwise or progressive worsening of neurological deficits, most commonly motor impairment, which is thought to reflect ongoing ischemia due to dynamic thrombo-atherosclerotic processes, hemodynamic instability, or progressive perforator occlusion. This clinical course is associated with worse functional outcomes and higher rates of long-term disability compared with stable lacunar infarcts.

From a therapeutic perspective, optimal acute management of BAD remains uncertain. Intravenous thrombolysis (IVT), while standard for acute ischemic stroke within the therapeutic window, appears to yield less consistent benefit in BAD compared to other stroke subtypes.

Given these uncertainties, this study aims to evaluate real-world treatment effectiveness of IVT compared with antiplatelet-based strategies in patients with imaging-confirmed BAD. In addition, the study investigates the potential role of early hemodynamic variability, particularly blood pressure fluctuations, as a modifiable factor influencing END and functional outcome.

This is an international, multicenter, retrospective observational cohort study conducted according to STROBE guidelines. Participating stroke centers contribute consecutively treated patients meeting predefined radiological and clinical criteria over a 15-year period. All included patients underwent standardized neuroimaging with MRI, allowing for consistent identification of infarct topography and exclusion of alternative stroke mechanisms.

Clinical data, imaging findings, acute treatment strategies, blood pressure profiles, and outcome measures are extracted from institutional stroke databases and anonymized prior to central analysis. Comparative effectiveness analyses will be performed to assess differences between treatment groups, with adjustment for baseline imbalances using appropriate statistical methods, including propensity score-based approaches.

Overall, this study seeks to address a gap in stroke literature by providing multicenter evidence on the comparative effectiveness of intravenous thrombolysis versus antiplatelet strategies in BAD, while simultaneously clarifying the prognostic significance of early hemodynamic changes in this under-recognized stroke subtype.

Primary outcome measures

• Favorable outcome (mRS 0-1) at three months. [Time frame: Three months after acute ischemic stroke treatment]
• Early neurological deterioration within 24-48 hours after symptom onset [Time frame: within 24-48 hours after acute ischemic stroke onset]
• Occurrence of symptomatic intracerebral hemorrhage. [Time frame: within three months after acute ischemic stroke treatment.]

Secondary outcome measures (1)

• Good functional outcome (mRS 0-2) [Time frame: three months after acute ischemic stroke treatment.]

Eligibility criteria

Inclusion criteria

• aged over 18 years, with acute ischemic stroke and symptom onset no more than 24 hours before admission, who were treated in one of the stroke units of the participating institutions.
• All enrolled patients must have undergone a cerebral MRI for inclusion:

• DWI lesion: single isolated deep subcortical stroke AND
• 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

• Typical recent small subcortical infarction (RSSI) (oval, <20mm in all axes)
• ≥ 50% stenosis on the parent artery (i.e., BA, MCA, or ICA)
• Stroke due to other clearly identified causes or possible cardioembolic etiology.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Austria · 4 centers

• Clinic Favoriten — Vienna
• Clinic Hietzing — Vienna
• Department of Neurology, St. John's Hospital, Vienna, Austria — Vienna
• Department of Neurology, Medical University of Vienna — Vienna

Germany · 3 centers

• Department of Neurology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin — Berlin
• Department of Neurology, Heidelberg University Hospital — Heidelberg
• Department of Neurology & Stroke, University of Tübingen — Tübingen

Switzerland · 1 center

• Department of Neurology, Universityhospital of Bern — Bern

Publications

• Naimi AI, Whitcomb BW. Estimating Risk Ratios and Risk Differences Using Regression. Am J Epidemiol. 2020 Jun 1;189(6):508-510. doi: 10.1093/aje/kwaa044. No abstract available. PMID 32219364
• Barow E, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Ford I, Galinovic I, Nickel A, Puig J, Roy P, Wouters A, Magnus T, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP Investigators. Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial. JAMA Neurol. 2019 Jun 1;76(6):64 PMID 30907934
• Xu J, Xu X, Wang H, He L, Liu Q, Du Y, Wang J. Dual Antiplatelet Therapy Plus Argatroban Prevents Early Neurological Deterioration in Branch Atherosclerosis Disease. Stroke. 2022 Jan;53(1):e19-e20. doi: 10.1161/STROKEAHA.121.036356. Epub 2021 Nov 17. PMID 34784740
• Liu B, Zhang H, Wang R, Qu H, Sun Y, Zhang W, Zhang S. Early administration of tirofiban after urokinase-mediated intravenous thrombolysis reduces early neurological deterioration in patients with branch atheromatous disease. J Int Med Res. 2020 May;48(5):300060520926298. doi: 10.1177/0300060520926298. PMID 32459110
• Wu X, Liu Y, Nie C, Kang Z, Wang Q, Sun D, Li H, Liu Y, Mei B. Efficacy and Safety of Intravenous Thrombolysis on Acute Branch Atheromatous Disease: A Retrospective Case-Control Study. Front Neurol. 2020 Jul 7;11:581. doi: 10.3389/fneur.2020.00581. eCollection 2020. PMID 32733357
• Kobayashi Y, Kondo Y, Yamamoto K, Hirayama S, Kuasano Y, Tazawa KI, Shimizu Y, Sato A, Sekijima Y. Tissue plasminogen activator for acute branch atheromatous disease exhibits transient improvement and worsening. J Neurol Sci. 2024 Oct 15;465:123201. doi: 10.1016/j.jns.2024.123201. Epub 2024 Aug 30. PMID 39217764
• Yamamoto Y, Ohara T, Hamanaka M, Hosomi A, Tamura A, Akiguchi I. Characteristics of intracranial branch atheromatous disease and its association with progressive motor deficits. J Neurol Sci. 2011 May 15;304(1-2):78-82. doi: 10.1016/j.jns.2011.02.006. Epub 2011 Mar 13. PMID 21402390
• Duan Z, Fu C, Chen B, Xu G, Tao L, Tang T, Hou H, Fu X, Yang M, Liu Z, Zhang X. Lesion patterns of single small subcortical infarct and its association with early neurological deterioration. Neurol Sci. 2015 Oct;36(10):1851-7. doi: 10.1007/s10072-015-2267-1. Epub 2015 Jun 2. PMID 26032577

Identifiers

NCT: NCT07299994 · 17823177

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗