The primary goal of the trial is to determine if the experimental arms (rivaroxaban or ticagrelor or both) are superior to the clopidogrel arm for lowering the 1-year rate of ischemic stroke, intracerebral hemorrhage, or vascular death.

The proposed study is relevant to public health because narrowing of brain arteries is one of the most common causes of stroke worldwide. Compelling evidence suggests novel antithrombotic medications could reduce the rate of stroke in patients with narrowed brain arteries. The proposed study will directly compare novel antithrombotic medications to standard care antiplatelet medications for preventing stroke and death from vascular causes in patients with narrowed brain arteries.

Inclusion Criteria:

• Acute focal symptoms or signs of any duration associated with imaging, pathological, or other objective evidence of arterial infarction OR clinical evidence of cerebral, spinal cord, or retinal focal arterial ischemic injury based on symptoms persisting greater than or equal to 24 hours that occurred within 30 days prior to randomization

• Index stroke is attributed to 70-99% stenosis (or flow gap on MRA) of a major intracranial artery (carotid artery, middle cerebral artery (M1 or M2), vertebral artery (V4), basilar artery, posterior cerebral artery (P1), or anterior cerebral artery (A1)) documented by CTA, MRA, or catheter angiography

• Modified Rankin Scale score of ≤ 4, at time of consent

• Ability to swallow pills

• At least 30 years of age, inclusive, at time of consent

• Subjects 30-49 years of age are required to meet at least ONE of the following additional criteria below to qualify for the study:

  1. diabetes treated with insulin for at least 15 years
  2. at least 2 of the following atherosclerotic risk factors: hypertension (BP > 140/90 or on antihypertensive therapy); dyslipidemia (LDL > 130 mg /dl or HDL < 40 mg/dl or fasting triglycerides > 150 mg/dl or on lipid lowering therapy); smoking; non-insulin dependent diabetes or insulin dependent diabetes of less than 15 years duration; any of the following vascular events occurring in a parent or sibling who was < 55 years of age for men or < 65 years of age for women at the time of the event: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, stroke, carotid endarterectomy or stenting, peripheral vascular surgery for atherosclerotic disease
  3. personal history of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, carotid endarterectomy or stenting, or peripheral vascular surgery for atherosclerotic disease
  4. any stenosis of an extracranial carotid or vertebral artery, another intracranial artery, subclavian artery, coronary artery, iliac or femoral artery, other lower or upper extremity artery, mesenteric artery, or renal artery that was documented by non-invasive vascular imaging or catheter angiography and is considered atherosclerotic
  5. aortic arch atheroma documented by non-invasive vascular imaging or catheter angiography
  6. any aortic aneurysm documented by non-invasive vascular imaging or catheter angiography that is considered atherosclerotic

• Negative pregnancy test in a female who has had any menses in the last 18 months and has not had surgery that would make her unable to become pregnant

• Subject is willing and able to return for all follow-up evaluations required by the protocol

• Subject is available by phone

• Subject understands the purpose and requirements of the study and can make him/herself understood

• Subject has provided informed consent (use of a LAR is not permitted)

Exclusion Criteria:

• Previous treatment of qualifying intracranial artery with a stent, angioplasty, or other mechanical device, including mechanical thrombectomy for the qualifying stroke, or plan to perform one of these procedures
• Plan to perform concomitant endarterectomy, angioplasty or stenting of an extracranial vessel tandem to the symptomatic intracranial stenosis
• Intracranial tumor (except meningioma) or any intracranial vascular malformation
• Thrombolytic therapy within 24 hours prior to randomization
• Progressive neurological signs within 24 hours prior to randomization
• History of spontaneous non-traumatic intracranial hemorrhage (parenchymal, subarachnoid, subdural, epidural)
• Intracranial arterial stenosis due to: arterial dissection; MoyaMoya disease; any known vasculitic disease; herpes zoster, varicella zoster or other viral vasculopathy; neurosyphilis; any other intracranial infection; any intracranial stenosis associated with CSF pleocytosis; radiation induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; benign angiopathy of central nervous system; postpartum angiopathy; suspected vasospastic process; reversible cerebral vasoconstriction syndrome (RCVS); suspected recanalized embolus
• Presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal atrial fibrillation, mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, myocardial infarction within three months, left atrial spontaneous echo contrast
• Known allergy or contraindication to aspirin, rivaroxaban, clopidogrel, or ticagrelor
• Uncontrolled severe hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 115 mm Hg), active peptic ulcer disease, major systemic hemorrhage within 30 days prior to randomization, active bleed or bleeding diathesis, platelets < 100,000, hematocrit < 30, INR > 1.5, clotting factor abnormality that increases the risk of bleeding, current alcohol or substance abuse, severe liver impairment (AST or ALT > 3 x normal, cirrhosis), or CrCl < 15 mL/min or on dialysis
• Major surgery (including stenting of any vessel; open femoral, aortic, or carotid surgery; or cardiac surgery) within previous 30 days prior to randomization or planned in the next 90 days after randomization
• Any condition other than intracranial arterial stenosis that requires the subject to take any antithrombotic medication other than aspirin (NOTE: exceptions allowed for subcutaneous heparin or enoxaparin for deep vein thrombosis (DVT) prophylaxis)
• Dementia or psychiatric problem that prevents the subject from following an outpatient program reliably
• Co-morbid conditions that may limit survival to less than 12 months
• Pregnancy or of childbearing potential and unwilling to use contraception for the duration of this study, or currently breastfeeding
• Current or anticipated concomitant oral or intravenous therapy with strong CYP3A4 inhibitors or CYP3A4 substrates that cannot be stopped for the course of this study
• Enrollment in another study that would conflict with the current study

1:1:1 treatment allocation