Predictors of symptomatic intracranial haemorrhage in off-label thrombolysis: an analysis of the Safe Implementation of Treatments in Stroke registry
S. Mundiyanapurath
Department of Neurology, University Hospital Heidelberg, Heidelberg
Search for more papers by this authorK. Hees
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
Search for more papers by this authorN. Ahmed
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm
Department of Neurology, Karolinska University Hospital-Solna, Stockholm, Sweden
Search for more papers by this authorN. Wahlgren
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm
Department of Neurology, Karolinska University Hospital-Solna, Stockholm, Sweden
Search for more papers by this authorL. Uhlmann
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
Search for more papers by this authorM. Kieser
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
Search for more papers by this authorP. A. Ringleb
Department of Neurology, University Hospital Heidelberg, Heidelberg
Search for more papers by this authorW. Hacke
Department of Neurology, University Hospital Heidelberg, Heidelberg
Search for more papers by this authorCorresponding Author
S. Nagel
Department of Neurology, University Hospital Heidelberg, Heidelberg
Correspondence: S. Nagel, Department of Neurology, University Hospital Heidelberg, Heidelberg 69120, Germany (tel.: 0049 6221 56 7075; fax: 0049 6221 56 7554; e-mail: [email protected]).Search for more papers by this authorS. Mundiyanapurath
Department of Neurology, University Hospital Heidelberg, Heidelberg
Search for more papers by this authorK. Hees
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
Search for more papers by this authorN. Ahmed
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm
Department of Neurology, Karolinska University Hospital-Solna, Stockholm, Sweden
Search for more papers by this authorN. Wahlgren
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm
Department of Neurology, Karolinska University Hospital-Solna, Stockholm, Sweden
Search for more papers by this authorL. Uhlmann
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
Search for more papers by this authorM. Kieser
Institute of Medical Biometry and Informatics, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
Search for more papers by this authorP. A. Ringleb
Department of Neurology, University Hospital Heidelberg, Heidelberg
Search for more papers by this authorW. Hacke
Department of Neurology, University Hospital Heidelberg, Heidelberg
Search for more papers by this authorCorresponding Author
S. Nagel
Department of Neurology, University Hospital Heidelberg, Heidelberg
Correspondence: S. Nagel, Department of Neurology, University Hospital Heidelberg, Heidelberg 69120, Germany (tel.: 0049 6221 56 7075; fax: 0049 6221 56 7554; e-mail: [email protected]).Search for more papers by this authorAbstract
Background and purpose
Intravenous thrombolysis (IVT) is the only approved pharmacological treatment for acute ischemic stroke. Off-label IVT for ischemic stroke is common. We aimed to analyse its safety in a large database.
Methods
This was a retrospective analysis of the safe implementation of treatments in stroke (SITS) thrombolysis registry with regard to 11 off-label criteria according to the European licence for alteplase. Symptomatic intracranial haemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study (ECASS II) definition and the National Institute of Neurological Disorders and Stroke definition as secondary safety endpoints. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed.
Results
Patients from 793 centres in 44 countries were included, mainly (95%) in Europe. A total of 56 258 patients who were treated with intravenous alteplase were included. Median age was 71 (IQR 61–78) years and median National Institutes of Health Stroke Scale score was 12 (IQR 7–17). A total of 16 740 (30%) patients received off-label IVT and 1037 (1.8%) patients suffered from SICH according to the SITS definition (SICH SITS). Median percentage of missing values per variable was 0.4%. The only two off-label criteria constituting independent positive and negative predictors for SICH SITS were high blood pressure (odds ratio, 1.39; 95% confidence interval, 1.08–1.80; P = 0.012) and minor stroke (odds ratio, 0.51; 95% confidence interval, 0.33–0.78; P = 0.002). Very severe stroke, previous stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and National Institute of Neurological Disorders and Stroke definitions.
Conclusions
Thrombolysis appears to be safe with regard to SICH for most of the off-label criteria, especially for minor stroke, but is risky in patients with high blood pressure. Individual risk–benefit evaluation should be performed.
Supporting Information
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| ene13507-sup-0001-Supinfo.docxWord document, 53.1 KB |
Table S1. Number of patients per centre with regard to all patients treated with intravenous thrombolysis. Table S2. Percentage of off-label thrombolysis in relation to the total number of patients treated with thrombolysis. Centres were divided into four quartiles according to their total number of patients treated with thrombolysis. Table S3. Baseline characteristics of patients with and without symptomatic intracranial haemorrhage according to the European Cooperative Acute Stroke Study (ECASS II). Values are presented as number (percentage) or median (interquartile range). Table S4. Baseline characteristics of patients with and without symptomatic intracranial haemorrhage according to the National Institute of Neurological Disorders and Stroke. Values are presented as number (percentage) or median (interquartile range). Table S5. Number of missing values per variable. The results of the validation and different sensitivity analyses can be found in the Supporting Information. Table S6. Multivariable logistic regression using symptomatic intracranial haemorrhage according to different definitions as dependent variable (complete case analysis). Table S7. Sensitivity multivariable analysis of all variables with P < 0.1 with regard to symptomatic intracranial haemorrhage according to Safe Implementation of Treatments in Stroke (SITS). Table S8. Sensitivity multivariable analysis of all variables with P < 0.1 with regard to symptomatic intracranial haemorrhage according to European Cooperative Acute Stroke Study (ECASS II). Table S9. Sensitivity multivariable analysis of all variables with P < 0.1 with regard to symptomatic intracranial haemorrhage according to National Institute of Neurological Disorders and Stroke (NINDS). Table S10. Sensitivity multivariable analysis with National Institutes of Health Stroke Scale as a continuous variable with regard to symptomatic intracranial haemorrhage according to Safe Implementation of Treatments in Stroke (SITS). In contrast to the primary analysis, the off-label criteria of very severe stroke and minor stroke were excluded due to collinearity. Table S11. Sensitivity multivariable analysis with National Institutes of Health Stroke Scale as a continuous variable with regard to symptomatic intracranial haemorrhage according to European Cooperative Acute Stroke Study (ECASS II). In contrast to the primary analysis, the off-label criteria of very severe stroke and minor stroke were excluded due to collinearity. Table S12. Sensitivity multivariable analysis with National Institutes of Health Stroke Scale as a continuous variable with regard to symptomatic intracranial haemorrhage according to National Institute of Neurological Disorders and Stroke. In contrast to the primary analysis, the off-label criteria of very severe stroke and minor stroke were excluded due to collinearity. Table S13. Sensitivity multivariable analysis including an independent variable ‘only one off-label criterion and fully on-label as reference’ with regard to symptomatic intracranial haemorrhage according to Safe Implementation of Treatments in Stroke (SITS). Table S14. Sensitivity multivariable analysis including an independent variable ‘only one off-label criterion and fully on-label as reference’ with regard to symptomatic intracranial haemorrhage according to European Cooperative Acute Stroke Study (ECASS II). Table S15. Sensitivity multivariable analysis including an independent variable ‘only one off-label criterion and fully on-label as reference’ with regard to symptomatic intracranial haemorrhage according to National Institute of Neurological Disorders and Stroke (NINDS). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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