Prof. Dr. med. MSc Mira Katan

A stroke is a life-threatening condition that occurs when the blood supply to part of the brain is cut off by either a blood clot (85% of cases) or a burst blood vessel. Strokes affect some 15-17 million people a year, and they are a leading cause of death and disability. Urgent treatment is therefore essential to save the patient’s life and prevent further damage to the brain. Due to the potential for long-lasting consequences, stroke care involves a lengthy, complex pathway requiring coordination among multiple healthcare professionals. Unfortunately, many patients experience impaired care due to poor coordination between their healthcare providers.

The UMBRELLA project aims to revolutionise the way we manage strokes by implementing a comprehensive approach that addresses gaps along the whole stroke care pathway, from diagnosis and emergency treatment, right through to rehabilitation and the prevention of further strokes.

At the heart of UMBRELLA is a federated data platform dubbed the ‘U-platform’. The project will harmonise real world stroke data from participating clinical centres to a common data model. These datasets will then be used to locally create and validate artificial intelligence (AI) algorithms designed to advance stroke diagnosis, risk prediction, and decision-making at different points in the stroke care pathway.

The new AI algorithms will undergo further training and testing on other datasets via a federated learning framework. This approach ensures the AI models benefit from being trained on multiple datasets, but because the data is not shared or pooled, security and privacy are ensured.

The project also aims to create standardised stroke management protocols and procedures and implement them across the participating clinical centres. These protocols will include the use of digital technologies to collect and visualise data, engage patients, and facilitate decision making at all stages of stroke care.

Finally, the project will develop a regulatory roadmap to secure the approvals needed to implement the project outputs in patient care. They will also establish a sustainability plan to ensure the continued existence of resources like the U-Platform beyond the end of the project.

Patients who suffered ischaemic stroke are at high risk for a recurrent cerebrovascular event. Despite all efforts in secondary prevention, stroke is still among the top causes for invalidity and death. Traditionally, risks for stroke recurrence are thought to be based on categorized stroke aetiologies and the amount of vascular risk factors. This concept however does not sufficiently reflect the complex pathophysiology and thus comes along with substantial issues. Rather, it appears probable that circulating mediators related to the extent of acute and chronic brain damage in concert with aetiological mechanisms and underlying comorbidities influence the risk for recurrent cerebrovascular events. With the CiRculating mEdiators of Stroke reCurrENce anD aetiOlogies (CRESCENDO) consortium, we aim to address this hypothesis. CRESCENDO will utilize existing biosample collections from a total of over 5,000 thoroughly evaluated patients at the three study sites in Hannover, Seville and Basel/Zurich. We on the one hand will investigate well-characterized biomarkers of cerebral damage, inflammation, immunothrombosis and stress in a hypothesis-driven approach and on the other hand explore predictive targets via a data-driven approach applying proteomics. The objective of this collaboration is to initiate a paradigm shift towards an integrated pathophysiology-based evaluation of individual cerebrovascular risks and to identify innovative approaches for secondary stroke prevention.

The DISTAL study is a SNSF funded randomized study investigating, whether endovascular therapy in addition to best medical therapy improves the long-term quality of life in patients with an acute stroke due to a medium distal vessel occlusion. It will allow a conclusion to be drawn as to whether this therapeutic strategy is beneficial or not.

Background: To prevent stroke recurrence we treat our patients based on the presumed underlying etiology, but in clinical practice we are still unable to identify the underlying cause in up to 30% of patients 1. Recent evidence suggests that some cryptogenic strokes may arise from cardiac thromboembolism that goes unrecognized because it has not manifested with atrial fibrillation (AF) yet2, 3. Mid-regional atrial natriuretic peptide (MRproANP) is highly associated with AF but beyond this, it is able to independently identify cardioembolic stroke etiology even in the absence of AF (adjusted OR of 2.1 (95%CI 1.11-3.97)). Moreover MRproANP was associated with future stroke risk after adjustment of manifest cardiac disease (adjusted HR of 3.5 (95%CI 1.6-7.5))4-6. MR-proANP seems to be a subtle marker of underlying atrial thromboembolism6 which may help identifying the biological distinct group who most likely benefits from direct oral anticoagulants even when AF is (not yet) detected. Methods: We propose to perform a multicenter biomarker guided, randomized, assessor blinded, clinical trial. Five hundred patients without known atrial fibrillation and an MRproANP level above 255 pmol/L will be randomized in a 1:1 ratio either to standard treatment (aspirin 100mg/d) or treatment with a direct oral anticoagulant (DOAC)). Patients in both treatment arms will receive standardized acute medical treatment as well as risk factor management. The primary outcome measure is a composite of major bleeding, recurrent stroke and/or vascular death within 1 year after the index ischemic stroke. Specific Aim: To test the hypothesis that a direct oral anticoagulant in MRproANP selected patients is superior to standard treatment with aspirin 100mg/d for the prevention of recurrent stroke and/or vascular death within one year in acute ischemic stroke patients without known atrial fibrillation.Significance: This trial seeks to optimize secondary prevention in patients with ischemic stroke using a blood biomarker to differentiate the underlying mechanism of stroke and thereby guide therapy. On one hand given the benefit of DOACs in patients with known AF this trial may offer a similar benefit to patients with stroke due to cardiac thromboembolism without detected AF. On the other hand given the risks of bleeding associated with anticoagulant drugs, and since not all strokes without detected AF are due to atrial thromboembolism it is essential to define as precisely as possible also the groups who would not benefit from their use. Therefore, our approach adheres well with the general effort toward precision medicine.

Background: At least 1 in 6 patients who survives a stroke will suffer another stroke within 5 years. For optimal secondary prevention directed at the underlying mechanism, an aetiological classification of stroke is critical. Even with a thorough evaluation, the aetiology of ischemic stroke remains “undetermined” (i.e. classified as cryptogenic stroke according to the classical TOAST criteria) or not evident but only “possible” or “probable” (according to the SSS TOAST-criteria) and thus in 25-39% of patients a specific secondary prevention cannot be initiated. The highest rates of stroke recurrence and mortality are seen in patients with cardioembolic and cryptogenic stroke. Patients initially diagnosed as cryptogenic stroke can, however, later be found to have a detectable cause of stroke, such as paroxysmal atrial fibrillation (AF) or symptomatic atherosclerotic disease (even if stenosis in initial exam was less than 50%). The use of rapidly measurable serum biomarkers for aetiologic diagnostic assessment on admission may enhance aetiologic classification and thus improve the implementation of optimal secondary prevention, patient outcome and benefit-cost ratio. Several promising candidate blood biomarkers have been described recently to be strongly and independently associated with cardioembolic stroke (CE) or large-artery atherosclerotic stroke (LAA). However no study simultaneously assessed the association of these blood biomarkers with the underlying aetiology and the hard endpoint of stroke recurrence as well as their incremental predictive value over existing prognostic and diagnostic clinical information on admission.Personal Research: In the past 5 years, I conducted patient-centered interdisciplinary (Department of Endocrinology and Neurology) clinical outcome studies focusing on neuroendocrine hormones as prognostic and diagnostic biomarkers in stroke patients. We investigated the prognostic value of neuroendocrine markers (e.g. copeptin, MRproANP, TSH, Cortisol etc.) for optimal risk stratification in acute ischemic stroke patients first in a large single center study (COSMOS n>500). Using this study as derivation set we aimed at validating these data and I performed as one of the primary investigators a multicenter study (the CoRisk Study) in over 1000 patients in collaboration with hospitals in Switzerland and Germany. Moreover I currently investigate promising prognostic inflammatory (e.g. LpPLA2) as well as neuroendocrine markers (e.g. Copeptin, MRproANP) and their association with increased risk of stroke also looking at stroke aetiology in one of the largest cohorts of stroke-free participants focused on stroke outcomes worldwide (n>3000; the Northern Manhattan Study, or NOMAS).Approach: We propose to prospectively evaluate the predictive value of the most promising serum biomarkers to identify treatable stroke etiologies on admission and risk of recurrence in 3000 consecutive incident ischemic stroke patients enrolled by 10 centers in Europe and the US. From these 3000 patients we estimate to include at least 750 individuals with a cryptogenic stroke classified according to the original TOAST classification 2 and 120 individuals when classified by the SSS-TOAST classification3. The clinical endpoints of the study are 1) recurrent stroke within one year, 2) all types of AF detected on admission or by prolonged ambulatory cardiac rhythm monitors, 3) presence of cerebrovascular atherosclerosis detected by ultrasound investigations and 4) new silent ischemic brain lesions and progression of chronic cerebral ischemic lesion volume detected by repeated magnetic resonance imaging (MRI and MRA) and (i.e. on admission and after 12 months). Aim 1: To determine whether the proposed biomarkers independently predict recurrent stroke among all patients. Hypothesis 1: Elevated levels of one or more of the proposed biomarkers will independently predict recurrent strokes during trial follow-up, assessed by structured interviews, as well as chart reviews 1 year after the index stroke.Aim 2: To determine whether CE biomarkers are associated with atrial fibrillation among all patients. Hypothesis 2: Baseline values of one or more of the proposed CE biomarkers will be independently associated with AF, including history of AF, AF detection at baseline, or AF detected during the follow up period by 21-day ambulatory cardiac rhythm monitors and structured interviews as well as chart reviews 1 year after the index stroke.Aim 3: To determine whether LAA biomarkers are associated with a) the presence of cerebrovascular atherosclerosis among all patients. Hypothesis 3: Baseline values of one or more of the proposed LAA biomarkers will be independently associated with the presence of extra and intracranial atherosclerosis among patients with ischemic stroke, assessed by duplex sonsography.Aim 4: To determine whether the proposed biomarkers will predict b) new silent strokes and c) progression of chronic cerebral ischemic lesion (white matter hyper-intensity) volume (WMHV) among cryptogenic stroke patients. Hypothesis 4: Baseline values of one or more of the proposed biomarkers will independently predict a) silent stroke b) progression of WMHV, during study follow-up, assessed by repeated magnetic resonance imaging (MRI) (on admission, and 1 year after the index stroke).Significance: Completion of the proposed study will answer the question of whether patients with higher levels of the selected biomarkers are at increased risk for recurrent events after acute ischemic stroke, and if the selected biomarkers can help to improve identifying patients for established effective secondary prevention treatments, allowing us to potentially reduce overall risk of recurrent stroke and thus improve quality of life.

Das Swiss Stroke Register (SSR) verwaltet seit 2014 standardisierte Daten von Patientinnen und Patienten mit aktutem Hirnschlag, Hirnblutung und weiteren zerebrovarkulären Erkrankungen. Aus ihm leiten sich zahlreiche Forschungsprojekte ab.

Das SSR wurde von der Schweizerischen Hirnschlaggesellschaft (SHG) in Auftrag gegeben. Sämtliche in der Hirnschlagtherapie zertifizierte Spitäler der Schweiz sind an das SSR angeschlossen und liefern laufend Daten von betroffenen Patientinnen und Patienten. Bisher wurden rund 112'000 Fälle im SSR erfasst. Jährlich kommen mehr als 10'000 Fälle hinzu.

Das Register ist eine der umfangreichsten Plattformen für multizentrische Forschungsprojekte, die schweizweit durchgeführt werden. Ziel ist die kontinuierliche Qualitätsverbesserung der Hirnschlagtherapie sowie der landesweiten Koordination der therapeutischen Versorgung. Die Koordination des Registers steht unter der Leitung von Prof. Mira Katan, Leitende Ärztin Neurologie und Leiterin der Stroke Unit am Universitätsspital Basel (USB).