Please select the eligibility criteria that correspond to the clinical trial below.
Title: Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation: Acute Stroke With Xarelto to Reduce Intracranial Bleeding, Recurrent Embolic Stroke, and Hospital Stay, Phase 2, Conceptual Multicenter Trial
Brief Summary: Rationale Acute ischemic stroke due to atrial fibrillation (AF) carries a high risk for early recurrence. In acute stage, guidelines recommend aspirin, but do not recommend anticoagulation due to the increased risk of intracranial bleeding. Since, aspirin has a limited efficacy of preventing recurrent stroke in AF, expert consensus suggests early anticoagulation in non-severe stroke with AF. The current practice for acute ischemic stroke patients with AF is delayed warfarin administration with aspirin use for non-minor stroke or immediate warfarin administration (sometimes with heparin bridging) for minor stroke. However, conventional anticoagulation with warfarin in acute ischemic stroke with AF has the following limitations: 1) risk of intracranial bleeding particularly in acute stage, 2) delayed action and transient paradoxical thrombogenic tendency due to the inhibition of protein C, resulting in the risk of early recurrent embolic stroke, and 3) prolongation of hospitalization waiting for full anticoagulation. In contrast, as compared to warfarin, rivaroxaban is advantageous for reduced risk of intracranial bleeding and immediate anticoagulation efficacy.

Goal The current trial will examine whether early initiation (within 5 days from stroke onset) of rivaroxaban as compared to conventional warfarin would reduce intracranial bleeding, recurrent embolic stroke, and hospital stay in patients with acute ischemic stroke due to AF.


Options:
A: Inclusion Criteria:

* Recent ESUS (between 7 days and 6 months), defined as:
* Recent ischemic stroke (including transient ischemic attack with positive neuroimaging) visualized by brain imaging that is not lacunar, and
* Absence of cervical carotid atherosclerotic stenosis\> 50% or occlusion, and
* No atrial fibrillation after ≥ 24-hour cardiac rhythm monitoring, and
* No intra-cardiac thrombus on either transesophageal or transthoracic echocardiography, and
* No other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)

Exclusion Criteria:

* Severely disabling stroke (modified Rankin score ≥4)
* Indication for chronic anticoagulation or antiplatelet therapy
* Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m\^2
B: Inclusion Criteria:

1. Signed Written Informed Consent
2. Males and Females over 18 years of age.
3. History of Nonvalvular Atrial Fibrillation (NVAF) by documentation in the medical history or newly diagnosed nonvalvular Atrial Fibrillation at time of study randomization by ECG, device or telemetry .
4. Diagnosis of TIA or small or medium ischemic stroke 0 to 48 hours from signs or symptoms.
5. Women of child-bearing potential must use a reliable method of contraception and must provide a negative pregnancy test at entry into the study and within 24 hours of study treatment initiation.
6. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Apixaban plus 5 half-lives (approximately 3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-treatment completion.
7. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with Apixaban plus 5 half-lives (approximately 3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment completion.
8. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.

Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly.

At a minimum, subjects must agree to the use of one method of highly effective contraception as listed below:

HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

* Male condoms with spermicide
* Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
* IUDs, such as ParaGard™
* Tubal ligation
* Vasectomy.
* Complete Abstinence

Exclusion Criteria:

1. Hemorrhagic stroke
2. Large ischemic stroke
3. History of major bleeding within the last 6 months from time of subject enrollment (e.g. GI bleed).
4. History of intracranial bleed

   a. Traumatic intracranial bleed within one year of randomization. (Traumatic ICH greater than one year of randomization is not an exclusion).
5. Current or history of bleeding disorders (e.g. blood dycrasias)
6. Blood Pressure of 180/100 mmHg on hypertensive therapy day of randomization per PI discretion 20.
7. Current illicit drug use and/or chronic alcohol use per PI discretion.
8. Severe liver disease (AST/ALT 2x upper limit).
9. Patients with kidney disease meeting criteria to take 2.5 mg twice daily who are taking strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin) .
10. Any other suspected etiology for stroke (e.g. ipsilateral carotid disease).
11. Greater than 3 Cerebral Micro-bleeds (CMB) on gradient recovery echo (GRE) or evidence of intracranial hemorrhage on CT at time of randomization. (SWI sequencing may be used if GRE sequencing is not obtainable)
12. Therapeutically anti-coagulated at time of admission (INR at admission greater than 2.0 on warfarin or took two consecutive doses of NOAC).
13. Absolute indication for use of warfarin only.( e.g. Mechanical Valve)
14. Absolute indication for anticoagulation prior to randomization window. (e.g. DVT)
15. Hemoglobin less than 9 gm/dl and/or platelet count less than 100 K/uL.
16. Requires dual antiplatelet therapy.
17. Daily use of NSAIDS
18. Pregnancy or lactation.
19. Any use of an investigational product within the past 30 days.
20. Prisoners or subjects who are involuntarily incarcerated.
21. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
22. Concurrent participation in another clinical study where use of an investigational product is used
C: Inclusion Criteria:

Patients of both sexes aged ≥ 18 years with the following 4 inclusion criteria:

* One of the 3 following ischemic events in the preceding 6 months:

  * Transient ischemic attack (TIA)
  * Non-disabling brain infarcts:

    * Inclusion within 6 months after onset
    * Duration of symptoms and signs greater than 24 hours
    * Neurological signs at the time of randomization with a Rankin Scale grade 3 or less
    * With normal computed tomography (CT) scan or CT scan showing a brain infarct (even hemorrhagic infarct)
  * Peripheral embolism
* Atherosclerotic plaque in the thoracic aorta is defined as wall thickness ≥ 4 mm where the protruding material is the largest, measured at transesophageal echocardiography with multiplane transducer or a plaque less than 4 mm but with mobile component.
* Informed consent signed
* Life expectancy \> 3 years

Exclusion Criteria:

* Other causes of embolism:

  * Cardiac: endocarditis, atrial fibrillation, intra-cardiac thrombus, valvular prosthesis, rheumatic valvulopathy, left ventricular aneurysm, or ejection fraction less than 25%
  * Atherosclerotic stenosis ipsilateral to the embolic territory: internal carotid artery stenosis greater than 70%, or severe (judgment of the investigator) intracranial stenosis, or scheduled carotid endarterectomy (in that case inclusion is possible 30 days after the procedure)
  * Uncommon causes: dissection, vasculitis, procoagulant state, or sickle cell disease
* Other exclusion criteria:

  * Intercurrent illness with life expectancy less than 36 months
  * Pregnancy and non-menopausal women
  * Unwillingness to participate
  * Poor medication compliance expected
  * Toxicomania
  * Absolute indication for anticoagulant therapy (e.g. atrial fibrillation, intracardiac thrombus, prosthetic valve)
  * Scheduled for carotid endarterectomy (randomization is possible 30 days after endarterectomy)
* CT scan with an intracranial lesion other than brain infarction (space occupying mass, intracranial hemorrhage)
* Transesophageal echocardiography (TEE) with plaque ≥ 4 mm in thickness distal to the supposed embolized artery (judgement of the investigator).
* Contraindication to clopidogrel, aspirin, and oral anticoagulants
D: Inclusion Criteria: All of below

* Acute ischemic stroke or TIA presumed to be cardioembolic origin (within 5 days from stroke onset) with mild severity: infarct size on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere
* Atrial fibrillation including paroxysmal atrial fibrillation: atrial fibrillation must be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before randomization. This could be obtained from a notation in the subject's record (e.g., medical chart, hospital discharge summary).
* Age ≥19 years
* Informed consent

Exclusion Criteria: Any of below

* Chronic renal failure (GFR less than 30ml/min) or severe hepatic impairment
* Significant hemorrhagic transformation (parenchymal hematoma type I or II by the ECASS definition)
* Stroke mechanism of presumed small vessel occlusion: single small subcortical infarct in the perforating artery territory
* Large hemispheric or cerebellar infarction; larger than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere
* Mechanical valve requiring warfarin therapy
* Active internal bleeding
* Prior history of symptomatic intracranial bleeding

  : patients with asymptomatic bleedings or microbleedings on MRI are eligible for inclusion
* Major surgery or major trauma within 30 days that might be associated with increased bleeding risk
* Clinically significant gastrointestinal bleeding within 6 months
* Intravenous tissue plasminogen activator use or mechanical embolectomy within 48 hours plus 'significant hemorrhagic transformation as described above (exclusion criteria 2)' or 'large hemispheric infarction or cerebellar infarction as described above (exclusion criteria 4)'

  : patients achieving successful reperfusion without hemorrhage nor large infarction are eligible for enrollment
* Severe anemia: hemoglobin \<10 g/dL
* Bleeding diathesis; thrombocytopenia (\<90,000/µL, prolonged PT (INR\>1.7)
* Sustained uncontrolled hypertension: SBP \>180 mmHg or DBP \>100 mmHg
* Severe devastating illness, such terminal cancer, hepatic failure; therefore, the participants have a life expectancy less than 6 months.
* Planned invasive procedure with potential for uncontrolled bleeding, including major surgery

Answer: D