Predictors of symptomatic intracranial haemorrhage in off-label thrombolysis: an analysis of the Safe Implementation of Treatments in Stroke registry

Eur J Neurol. 2018 Feb;25(2):340-e11. doi: 10.1111/ene.13507. Epub 2017 Dec 2.


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.

Keywords: intravenous thrombolysis; ischemic stroke; off-label; symptomatic intracranial haemorrhage.

Publication types

  • Multicenter Study

MeSH terms

  • Aged
  • Cerebral Hemorrhage* / chemically induced
  • Cerebral Hemorrhage* / epidemiology
  • Europe / epidemiology
  • Female
  • Fibrinolytic Agents* / adverse effects
  • Fibrinolytic Agents* / standards
  • Humans
  • Intracranial Hemorrhages* / chemically induced
  • Male
  • Middle Aged
  • Off-Label Use* / standards
  • Off-Label Use* / statistics & numerical data
  • Registries*
  • Retrospective Studies
  • Stroke* / drug therapy
  • Stroke* / epidemiology
  • Thrombolytic Therapy* / adverse effects
  • Thrombolytic Therapy* / standards
  • Thrombolytic Therapy* / statistics & numerical data
  • Tissue Plasminogen Activator* / adverse effects
  • Tissue Plasminogen Activator* / standards


  • Fibrinolytic Agents
  • Tissue Plasminogen Activator