Clinical Characteristics and Outcome of Patients With Hemorrhagic Transformation After Intravenous Thrombolysis in the WAKE-UP Trial

Someone needs to be identified to do the followup research how to identify those at risk for this. Research like this needs to be followed up. But with NO STROKE LEADERSHIP nothing will occur.  

Clinical Characteristics and Outcome of Patients With Hemorrhagic Transformation After Intravenous Thrombolysis in the WAKE-UP Trial

Märit Jensen^1*, Eckhard Schlemm¹, Bastian Cheng¹, Iris Lettow¹, Fanny Quandt¹, Florent Boutitie^2,3,4, Martin Ebinger^5,6, Matthias Endres^5,7,8,9, Jochen B. Fiebach⁵, Jens Fiehler¹⁰, Ivana Galinovic⁵, Vincent Thijs^11,12, Robin Lemmens^13,14,15, Keith W. Muir¹⁶, Norbert Nighoghossian¹⁷, Salvador Pedraza¹⁸, Claus Z. Simonsen¹⁹, Christian Gerloff¹ and Götz Thomalla¹

• ¹Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
• ²Hospices Civils de Lyon, Service de Biostatistique, Lyon, France
• ³Université Lyon 1, Villeurbanne, France
• ⁴CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
• ⁵Centrum für Schlaganfallforschung Berlin (CSB), Charité—Universitätsmedizin Berlin, Berlin, Germany
• ⁶Neurologie, Medical Park Berlin Humboldtmühle, Berlin, Germany
• ⁷Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
• ⁸German Center for Neurodegenerative Disease (DZNE), Partner Site Berlin, Berlin, Germany
• ⁹German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
• ¹⁰Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
• ¹¹Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia
• ¹²Austin Health, Department of Neurology, Heidelberg, VIC, Australia
• ¹³Department of Neurology, University Hospitals Leuven, Leuven, Belgium
• ¹⁴Department of Neurosciences, Experimental Neurology, KU Leuven—University of Leuven, Leuven, Belgium
• ¹⁵VIB, Laboratory of Neurobiology, Center for Brain & Disease Research, Leuven, Belgium
• ¹⁶Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom
• ¹⁷Department of Stroke Medicine, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Lyon, France
• ¹⁸Department of Radiology, Institut de Diagnostic per la Image (IDI), Hospital Dr. Josep Trueta, Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain
• ¹⁹Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

Background: Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome.

Methods: We performed a post-hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0–1 at 90 days.

Results: Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28–3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05–1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01–1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00–1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57–5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01–1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93–6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05–0.86]), while HI was not.

Conclusion: Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window.

Introduction

Hemorrhagic transformation (HT) represents an important complication of intravenous thrombolysis with alteplase for acute ischemic stroke. However, HT of ischemic stroke can show a wide range from small petechiae with no clinical impact to massive parenchymal hematoma with space-occupying effect associated with neurological deterioration. The following four subtypes of HT have been distinguished radiologically: hemorrhagic infarction type 1 (HI1; scattered small petechiae, no mass effect), hemorrhagic infarction type 2 (HI2; confluent petechiae, no mass effect), parenchymal hemorrhage type 1 (PH1; hematoma within infarcted tissue, occupying < 30%, no substantive mass effect) and parenchymal hemorrhage type 2 (PH2; hematoma occupying 30% or more of the infarcted tissue, with obvious mass effect) (1). In addition, intracerebral hemorrhage outside infarcted brain tissue or intracranial-extracerebral hemorrhage is considered a separate category, including subarachnoidal hemorrhage and subdural hematoma. The clinical significance of different types of HT after thrombolysis is a matter of debate (2). While there is no doubt that massive HT, meeting criteria of PH2, is likely to be associated with clinical worsening, mere hemorrhagic infarction (HI) may also be understood as a marker of successful recanalization into partially ischemic damage with no adverse clinical effect (3, 4). Previous work has suggested a different pathogenesis for HI and PH. While HI might be a clinically irrelevant epiphenomenon of ischemic damage and reperfusion, PH appears to be related to biological effects of alteplase and other pre-existing pathologic conditions and also carries the potential of clinical deterioration (4). At the same time, it is still uncertain how—if at all—patients at high risk of severe intracerebral hemorrhage after thrombolysis can be identified beforehand based on clinical or imaging characteristics. In the present study, our first objective was to identify possible clinical and imaging parameters that predict HT after acute ischemic stroke. Second, we aimed to study the functional outcome of patients with different types of HT to get further insights into the clinical significance of HT after intravenous thrombolysis.