Please select the eligibility criteria that correspond to the clinical trial below.
Title: Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation
Brief Summary: The purpose of this study is to evaluate if Apixaban will decrease the complication of having another stroke for people who have atrial fibrillation if initiated earlier than standard of care.


Options:
A: Inclusion Criteria:

* Disabling Ischemic stroke symptoms with onset \< 3 hours treated with IV rt-PA by local standards\*.

  \* or ≤ 4.5 hours according to local standard of care.
* NIHSS ≥ 10\* or any NIHSS with an intracranial clot should be demonstrated on neurovascular imaging (TCD or CTA) in any one of the following areas: distal internal carotid artery (ICA) carotid artery (CA), middle cerebral artery (MCA - M1 or M2), posterior cerebral artery (PCA - P1 or P2), distal vertebral or basilar artery.
* TCD criteria: Thrombolysis in brain ischemia (TIBI) 0, 1, 2 or 3 - CT-Angiogram: thrombolysis in myocardial ischemia (TIMI) 0 or 1 \* NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated.
* For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2.
* Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication.
* Signed (written) informed consent by the patient or the patient's legal representative and/or guardian.

Exclusion Criteria:

* Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalization.
* Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit.
* National institute health stroke scale (NIHSS) Level of Consciousness score (1a) ≥ 2.
* Pre-existing disability with mRS ≥ 2.
* CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory.
* Any evidence of clinically significant bleeding, or known coagulopathy.
* INR \>1.5.
* Patients with an elevated activated partial thromboplastin time (aPTT) greater than the upper limit of normal
* Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran).
* Heparin flush required for an IV line. Line flushes with saline only.
* Any history of intra-cranial hemorrhage, known arteriovenous -malformation or unsecured cerebral aneurysms.
* Significant bleeding episode \[e.g. gastrointestinal (GI) or urinary tract\] within the 3 weeks before study enrollment.
* Major surgery or serious trauma in last 2 weeks.
* Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks.
* Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months.
* Uncontrolled hypertension \[Systolic blood pressure (SBP) \> 185 mmHg or diastolic blood pressure (DBP) \>110 mmHg\] that does not respond to intravenous anti-hypertensive agents.
* Surgical intervention (any reason) anticipated within the next 48 hours.
* Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse.
* Abnormal blood glucose \<50 mg/dL (2.7 mmol/L).
* History of primary or metastatic brain tumor.
* Current platelet count \< 100,000/mm3.
* Life expectancy \< 3 months.
* Patient who, in the judgment of the investigator, needs to be on concomitant (i.e., during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, unfractionated heparin (UFH), low molecular weight heparin (LMWH), defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, glycoprotein llb/llla (GPIIb/IIIa) inhibitor or warfarin.
* Participated in any investigational study within 30 days before the first dose of study medication.
* Known hypersensitivity to Argatroban or its agents.
* Additional exclusion criteria if patient presents between 3-4.5 hours:

  1. Age \>80
  2. Currently taking oral anticoagulants (regardless of INR)
  3. A history of stroke and diabetes.
  4. NIHSS \> 25.
B: Inclusion criteria:

* Written informed consent in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and local legislation and/or regulations
* Confirmed diagnosis of Cerebral Venous or dural sinus thrombosis (CVT), with or without intracranial haemorrhage
* Completion of anticoagulation therapy for 5-15 days which has been administered until randomisation; anticoagulation must include full-dose low molecular weight heparin or unfractionated heparin
* Eligibility for treatment with an oral anticoagulant
* Further inclusion criteria apply

Exclusion criteria:

* Cerebral Venous or dural sinus thrombosis (CVT) associated with central nervous system infection or due to head trauma
* Planned surgical treatment for CVT
* Conditions associated with increased risk of bleeding
* History of symptomatic non-traumatic intracranial haemorrhage with risk of recurrence according to Investigator judgment
* Treatment with an antithrombotic regimen for an indication other than CVT and requiring continuation of that treatment for the original diagnosis without change in the regimen
* Severe renal impairment
* Active liver disease
* Pregnancy, nursing or planning to become pregnant while in the trial
* Further exclusion criteria apply
C: Inclusion Criteria:

* Adult patients (≥ 18 years) with acute ischemic stroke and atrial fibrillation
* Eligible and willing to start (or re-start) NOAC
* Registered in The Swedish Stroke Register
* Signed informed consent

Exclusion Criteria:

* Contraindication to NOAC (e.g. ongoing bleeding, mechanical heart valve prosthesis)
* Ongoing therapy with NOAC (without ≥2 days interruption at index stroke)
* International normalized ratio (INR)\>1.7
* No second brain imaging (CT/MRI) after thrombolysis/thrombectomy
* Previous randomization in the TIMING study
D: 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

Answer: D