Multicentre (national, Germany), randomized (2x2 factorial), open, parallel group, active controlled, efficacy study (phase III)

Based on the previous data, ATTICUS is designed as multicentre, national, parallel group, active controlled, phase III randomized (2x2 factorial), clinical trial to demonstrate the superiority of apixaban against the current standard of treatment (acetylsalicylic acid) for the longterm treatment after ESUS. ATTICUS will follow a dynamic treatment protocol implementing conversion from the acetylsalicylic acid arm to the apixaban arm in case of detection of relevant episodes of AF during the course of the study. ATTICUS is designed to test the superiority over acetylsalicylic acid to reduce new ischemic lesion detected by FLAIR/DWI MRI.

Inclusion criteria Must be ≥ 18 years at the time of signing the informed consent.

• ESUS must be defined according to following criteria:

  • Stroke detected by CT or MRI that is not lacunar
  • Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischaemia
  • No major-risk cardioembolic source of embolism
  • No other specific cause of stroke identified

• * At least one of the following non-major but suggestive risk factors for cardiac embolism:

  • LA size >45mm (parasternal axis)
  • spontaneous echo contrast in LAA
  • LAA flow velocity <=0.2m/s
  • atrial high rate episodes
  • CHA2DS2-Vasc score >=4
  • persistent foramen ovale

• Understand and voluntarily sign an informed consent document

• Women of childbearing potential (WOCBP) must be using an adequate method of contraception.

Exclusion Criteria:

• History of hypersensitivity to the investigational medicinal product
• Participation in other clinical trials or observation period of competing trials.
• Arteria cerebri media stroke affecting > 30% of c o r r e s p o n d i n g territory
• Diagnosis of haemorrhage or other pathology,
• Clear indication for anticoagulation
• Inability to control following risk factors for Hemorrhagic Transformation of fresh cerebral Infarction (HTI) during index hospital stay: presence of HTI at the time of anticoagulation, blood pressure >140 mmHg systolic, abnormal blood glucose Clear indication for dual antiplatelet therapy
• Clear stroke-/non-stroke-indication for concomitant long-term therapy with antiplatelets (e.g. acetylsalicylic acid (ASA), Clopidogrel, or Prasugrel) or with non-steroidal anti-inflammatory drugs (NSAID).
• Concomitant systemic therapy with strong inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. azole antimycotics and human immunodeficiency virus (HIV)-protease inhibitors.
• Contraindication to investigational medications
• Planned or likely therapy with fibrinolytic agents within 48 hours of first study medication
• History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding
• Gastrointestinal bleed or major surgery within 3 months
• Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months
• TIA or minor stroke induced by angiography or surgery
• Severe non-cardiovascular comorbidity with life expectancy < 3 months
• Severe renal failure, defined as Glomerular Filtration Rate (GFR) <15ml/min
• Severe hepatic insufficiency (Child-Pugh score B to C),
• Active liver disease,
• Contraindications against performance of MRI (pacemaker/ICD), previous implantation non-MRI capable protheses
• Patients considered unreliable by the investigator, or having a life expectancy less than the expected duration of the trial