Safety and Efficacy of Intravenous Thrombolysis in Patients With Ischemic Stroke and Direct Oral Anticoagulants Intake

• Tenecteplase or Alteplase (Drug): Patients randomized to intravenous thrombolysis (IVT) treatment will receive intravenous Tenecteplase or Alteplase.

Primary outcomes

• Modified Rankin Scale (mRS) [90 days +/- 2 weeks after randomization]: Modified Rankin Scale is a scale that runs from 0-6, running from perfect health without symptoms (0) to death (6).

Secondary outcomes

• Dichotomized modified Rankin Scale (mRS) 0-2 (good functional outcome) [90 days +/- 2 weeks post-randomization]: Modified Rankin Scale is a scale that runs from 0-6, running from perfect health without symptoms (0) to death (6).
• Change from baseline in stroke severity (National Institutes of Health Stroke Scale, NIHSS) [24 +/- 12 hours after Intervention]: The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. Thus, 0 (minimum score) means "no symptoms", whereas 42 (maximum score) means "severe stroke".
• Health-related Quality of Life (EuroQol 5D-3L questionnaire) [90 days +/- 2 weeks post-randomization]: The EuroQol 5D-3L (EuroQol 5 Dimensions with each 3 Levels) measures health-related Quality of Life.

Other outcomes

• Rate of Symptomatic intracranial hemorrhage [Within the first 36 hours post-randomization]: Observed in clinical imaging
• Rate of Major extracranial bleeding [Within the first 24 hours post-randomization]: Defined as clinically overt bleeding that is accompanied by one or more of the following (according to International Society on Thrombosis and Haemostasis definitions): * Decrease in haemoglobin of ≥ 2g / dl over a 24-hour period * Transfusion of ≥ 2 units of packed red blood cells * Occurring in a critical part of the body (intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal) * In order for bleeding (e.g. gastrointestinal) in a critical area or organ to be classified as a major extracranial bleeding it must be associated with a symptomatic clinical presentation.
• All-cause mortality [Up to 7 to 10 days after admission or until discharge, usually 2 weeks after admission]: Death from any cause

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Informed consent (deferred consent when possible according to national legislation)
* AIS eligible to receive intravenous alteplase/tenecteplase as per standard of care disabling according to the judgement of the treating physician
* DOAC ingestion within 48 hours prior to enrollment, or patient with an ongoing prescription of DOAC but exact time point of last intake is unknown.
* Either

  * Can be randomized within 4 hours 15 minutes and treated within 4 hours 30 minutes of last known well time OR
  * MRI showing a pattern of "DWI-FLAIR-mismatch", i.e. acute ischemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischemic lesion ≤4.5 hours of age AND Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening).

Exclusion Criteria:

* Contra-indications to IVT by the current standard of care of the treating physicians with the exception of recent DOAC intake as specified above.
* Intended reversal by specific or unspecific reversal agents
* Pregnancy or lactating women. To be reasonable sure to exclude women with ongoing pregnancy, women are not considered of childbearing potential if they fulfill the following criteria

  * Age > 55 years OR
  * Age < 55 years and at least 12 months since last menstrual period OR
  * Have had a documented surgical sterilization
* Patient < 18 years of age (since the benefit of IVT is unproven in this population)

Since the benefit of IVT might be smaller in patients in which additional endovascular treatment is planned, the investigators will cap patients with intended mechanical thrombectomy at 20% of the trial population. If this number is reached, the following additional exclusion criterion will be applied:

* Intended treatment with endovascular reperfusion strategies

9 more sites not listed.

• Thomas Meinel, MD, PhD, Study director, Insel Gruppe AG, University Hospital Bern