Please select the eligibility criteria that correspond to the clinical trial below.
Title: Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TOACT)
Brief Summary: Background: Endovascular thrombolysis, with or without mechanical clot removal (ET), may be beneficial for a subgroup of patients with cerebral venous sinus thrombosis (CVT), who have a poor prognosis despite treatment with heparin. Published experience with ET is promising, but only based on case series and not on controlled trials.

Objective: The main objective of the TO-ACT trial is to determine if ET improves the functional outcome of patients with a severe form of CVT

Study design: The TO-ACT trial will be designed as a multi-centre, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

Study population: Patients are eligible if they have a radiologically proven CVT, a high probability of poor outcome (defined by presence of one or more of the following risk factors: mental status disorder, coma, intracranial hemorrhagic lesion or thrombosis of the deep cerebral venous system) and the responsible physician is uncertain if ET or standard anti-coagulant treatment is better.

Intervention: Patients will be randomized to receive either ET or standard therapy (therapeutic doses of heparin). ET consists of local application of alteplase or urokinase within the thrombosed sinuses, and/or mechanical thrombectomy. Glasgow coma score, NIH stroke scale and relevant laboratory parameters will be assessed at baseline.

Endpoints: The primary endpoint is the modified Rankin scale (mRS) at 12 months. The most important secondary outcomes are the mRS, mortality and recanalization rate at 6 months. Major intra- and extracranial hemorrhagic complications within one week following the intervention are the principal safety outcome. Results will be analyzed according to the "intention-to-treat" principle. Assessment of study endpoints will be carried out according to standardized questionnaires by a blinded neurologist or research nurse who is not involved in the treatment of the patient.

Study size: To detect a 50% relative reduction in mRS≥2 (from 40 to 20%), 164 patients (82 in each treatment arm) have to be included (two-sided alpha, 80% power).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Included patients may benefit directly from ET. Complications of ET, most notably intracranial hemorrhages, constitute the most important risk of the study.


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:

1. Cerebral venous thrombosis, confirmed by cerebral angiography (with intra-arterial contrast injection), magnetic resonance venography or computed tomographic venography.
2. Severe form of CVT with a high chance of incomplete recovery, as defined by the presence of one or more of the following risk factors

   1. Intracerebral hemorrhagic lesion due to CVT
   2. Mental status disorder
   3. Coma (Glasgow coma scale \< 9)
   4. Thrombosis of the deep cerebral venous system
3. Uncertainty by the treating physician if ET or standard heparin therapy is the optimal therapy for the patient.

Exclusion Criteria:

* Age less than 18 years
* Duration from diagnosis to randomization of more than 10 days
* Recurrent CVT
* Any thrombolytic therapy within last 7 days
* Pregnancy (women in the puerperium may be included)
* Isolated cavernous sinus thrombosis
* Isolated intracranial hypertension (without focal neurological signs, with the exception of papilloedema and 6th cranial nerve palsy)
* Cerebellar venous thrombosis with 4th ventricle compression and hydrocephalus, which requires surgery
* Contraindication for anti-coagulant or thrombolytic treatment

  1. documented generalized bleeding disorder
  2. concurrent thrombocytopenia (\<100 x 10E9/L)
  3. documented severe hepatic or renal dysfunction, that interferes with normal coagulation
  4. uncontrolled severe hypertension (diastolic \> 120 mm Hg)
  5. known recent (\< 3 months) gastrointestinal tract hemorrhage (not including he¬morrhage from rectal hemorrhoids)
* Any known associated condition (such as terminal cancer) with a poor short term (1 year) prognosis independent of CVT
* Clinical and radiological signs of impending transtentorial herniation due to large space-occupying lesions (e.g. large cerebral venous infarcts or hemorrhages)
* Recent (\< 2 weeks) major surgical procedure (does not include lumbar puncture) or severe cranial trauma
* Known allergy against contrast fluid used during endovascular procedures or the thrombolytic drug used in that particular centre
* Previously legally incompetent prior to CVT
* No informed consent
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:

* ischemic stroke
* female or male gender
* mRS (modified Rankin Scale) 0-1 (min one month before the event)
* NIHSS ≥ 6 and ≤ 25
* Age: 18-80 years
* initiation of therapy in the interval from 4.5 to 24 hours from onset of symptoms of ischemic stroke
* focal neurological deficit of at least 30 min, which was significantly obviously does not disappear before treatment
* patient will participate voluntarily and signed informed consent. Informed consent will be obtained from each patient, guardian or close relative
* patients who are unable to sign, but who are able to understand what means to participate in the study, may give informed consent through eyewitness
* willingness and ability to comply with the protocol

Exclusion Criteria:

* intracranial hemorrhage confirmed by CT scan
* CT image heavy and extensive focal cerebral ischemia
* lacunar syndrome
* epileptic seizure at the beginning of ischemic stroke
* previous or planned treatment with intravenous, intra-arterial thrombolysis, mechanical recanalization or ultrasound assisted thrombolysis
* stroke, myocardial infarction, head trauma in the last 3 months
* tromboctov count below 100 000/mm ³
* therapeutically uncontrolled blood pressure: systolic blood pressure\> 185 mmHg or diastolic blood pressure\> 110 mmHg
* therapeutically uncontrolled blood glucose ˂ 2.77 or\> 22.15 mmol / l
* Known bleeding diathesis, other coagulopathies, severe hepatopathy, severe nephropathy
* patients receiving oral anticoagulants
* current or previous life-threatening bleeding
* major surgery less than 2 weeks ago
* known malignancy
* active TB
* pregnancy
* allergy to Heparin or Fraxiparine
* known alcohol abuse and / or drugs
* active participation in another clinical study

Answer: B