Please select the eligibility criteria that correspond to the clinical trial below.
Title: IV vs. IA tPA (Activase) in Acute Ischemic Stroke With CTA Evidence of Major Vessel Occlusion
Brief Summary: Stroke is the third leading cause of death in the United States, responsible for 158,488 deaths in 1998 (American Heart Association). Nationwide, each year, an estimated 600,000 to 750,000 people suffer a new or recurrent stroke. Cerebral infarction comprises 80% of all strokes and is the result of a complex series of cellular metabolic events that occur rapidly after interruption of blood flow to a region of the brain. The extent of the brain damage is dependent on the duration and severity of the cerebral ischemia. Acute thrombus formation or migration is the principal cause of blood flow interruption in at least 75% of cerebral infarctions. In several animal models of focal cerebral ischemia, restoration of cerebral blood flow within two to six hours after initial occlusion has been associated with smaller volumes of cerebral infarction and improved functional outcome. An effective way of dissolving the thrombus is by administration of recombinant tissue plasminogen activator or Activase (Alteplase, rt-PA), which promotes the proteolytic action of plasmin from plasminogen at the site of a clot. In this study, the drug, Activase, will be administered in subjects with acute ischemic stroke (AIS) intravenously (IV) or by local intra-arterial (IA) injection. The use of the intravenous administration within 3 hours of stroke symptom onset is FDA approved whereas the intra-arterial administration, despite evidence of potential benefit, is not currently FDA approved. Although not FDA approved, this study will evaluate the effectiveness of IA thrombolysis with Activase, used in AIS because of its higher rate of recanalization , potential expansion of the time window out to 6 hours, and lower doses of thrombolytic agent used compared with systemic or intravenous Activase. The study is designed to test the feasibility and provide preliminary safety data regarding the relative benefits and risks of IA Activase as compared to IV Activase when administered per the NINDS rt-PA stroke study protocol, i.e. randomized within 3 hours of onset of symptoms of ischemic stroke then treated within 3 hours in the IV Activase arm and within 4 hours in the IA Activase arm.


Options:
A: Inclusion criteria:

* Sudden focal neurological deficit attributable to a stroke
* Clearly defined time of onset, allowing initiation of intravenous treatment within 3 hours of symptoms onset and intra-arterial treatment within 6 hour of symptoms onset.
* Age between 18 and 80 years

Exclusion criteria:

* Disability preceding stroke consistent with a modified Rankin scale score of 2-4 (see glossary for Rankin scale)
* Coma at onset
* Severe stroke as assessed clinically (e.g. NIHSS\>25)
* Rapidly improving neurological deficit or minor symptoms
* Seizure at onset of stroke
* Clinical presentation suggestive of a subarachnoid hemorrhage (even of CT scan is normal) or condition after subarachnoid hemorrhage from aneurysm
* Previous history of or suspected intracranial hemorrhage
* Previous history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
* Septic embolism, bacterial endocarditis, pericarditis
* Acute pancreatitis
* Arterial puncture at a non compressible site (e.g. subclavian or jugular vein puncture) or traumatic external heart massage or obstetrical delivery within the previous 10 days
* Another stroke or serious head trauma within the preceding 3 months
* Major surgery or significant trauma in past 3 month
* Urinary tract hemorrhage within the previous 21 days
* Documented ulcerative gastrointestinal disease during the last 3 months, esophageal varices, arterial-aneurysm, arterial/venous malformations • Neoplasm with increased bleeding risk
* Severe liver disease, including hepatic failure, cirrhosis, portal hypertension (esophageal varices) and active hepatitis
* Current therapy with intravenous or subcutaneous heparin or oral anticoagulants (e.g. warfarin sodium) to rise the clotting time
* Known hereditary or acquired hemorrhagic diathesis, baseline INR greater than 1.5, aPTT more than 1.5 times normal, or baseline platelet count less than 100,000 per cubic millimeter
* Baseline blood glucose concentrations below 50 mg per deciliter (2.75 mm/L) or above 400 mg per deciliter
* Hemorrhagic retinopathy, e.g. in diabetes (vision disturbances may indicate hemorrhagic retinopathy)
* Any history of prior stroke and concomitant diabetes
* Prior stroke within the last 3 months
* Known contrast sensitivity
* Severe uncontrolled hypertension defined by a blood pressure ≥ 185 mmHg systolic or diastolic ≥ 110 mm Hg in 3 separate occasions at least 10 minutes apart or requiring continuous IV therapy
* Prognosis very poor regardless of therapy; likely to be dead within months.
* Unlikely to be available for follow-up (e.g., no fixed home address, visitor from overseas).Any other condition which local investigators feels would pose a significant hazard in terms of risk/benefit to the patient, or if therapies are impracticable.

Computed tomographic (CT) scan exclusion criteria

* Intracranial tumors except small meningioma
* Hemorrhage of any degree
* Acute infarction (since this may be an indicator that the time of onset is uncorrected
B: Inclusion Criteria:

* Patients with at least a serious, measurable deficit on the NIH Stroke Scale in language (aphasia score \> 1), motor power (arm or leg \> 1), vision (best visual score \> 2), or attention (attention score \> 2). Thus eligible patients may have a minimum total score of 1 if the deficit is in language or motor power. There is no maximum score that is exclusionary; even patients with severe hemispheric or brainstem deficits will be eligible, as is current practice with intravenous rt-PA. Patients with all ischemic stroke types and in all vascular distributions are eligible.
* Must arrive at participating hospital and treatment begun within 3 hours of the onset of symptoms. Patients awakening with new symptoms must use the time last observed to be normal and awake and the total time cannot exceed three hours prior to treatment as the time of onset.
* Must be 18 years of age or older.

Exclusion Criteria:

* Patients with a) minor stroke symptoms (e.g., sensory loss, ataxia, dysarthria, or facial weakness alone) or b) major symptoms which are rapidly improving by the time of treatment.
* Patients for whom a complete NIH Stroke Score cannot be obtained (e.g., intubated patients or complete amputees).
* Patients with evidence of intracranial hemorrhage on pretreatment CT scan.
* Patients with a clinical presentation that suggests subarachnoid hemorrhage, even if the initial CT scan is normal.
* Patients who are known or suspected to be pregnant.
* Patients with a known bleeding diathesis or patients with a platelet count \< 100,000. For patients who are taking oral Warfarin (Coumadin), the results of the pretreatment International Normalized Ratio (INR) must be available prior to treatment and must be
* \</= 1.4. Patients who have received heparin within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible. Patients who have received low molecular weight heparin or heparinoid within 24 hours are also excluded.
* Patients with major surgery or serious trauma excluding head trauma within 14 days or serious head trauma within 3 months.
* Patients with a history of gastrointestinal or urinary tract hemorrhage in the previous 21 days.
* Patients with an arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days.
* Patients who, on repeated measurement, have a systolic blood pressure \> 185, or a diastolic blood pressure \> 110 mmHg when treatment is to begin, or require aggressive treatment to reduce blood pressure to within these limits.
* Patients with a history of stroke in the previous 3 months or have ever had an intracranial hemorrhage considered to put them at increased risk for intracranial hemorrhage.
* Patients with a serious medical illness likely to interfere with treatment or treatment might adversely affect that illness.
* Patients with abnormal blood glucose thought to account for the neurological deficit.
* Patients with a clinical presentation consistent with acute myocardial infarction or patients with presentation suggesting post-myocardial infarction pericarditis.
* Patients with a seizure at onset of stroke thought to be presenting with post-ictal paralysis mimicking stroke.
* Patients with pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations.
* Patients who have received any other investigational drug within 14 days.
* Patients who have large areas (greater than one lobe) of obvious low density on the baseline CT scan will be presumed to have had ongoing cerebral ischemia for greater than 3 hours, and will, therefore, be excluded. Patients with subtle early signs of cerebral infarction (e.g., sulcal effacement, blurring of the grey-white junction, asymmetry of the basal ganglia, insular ribbon sign, and others) and the dense artery sign on baseline CT scan will be eligible. Similarly, evidence of previous remote cerebral infarction on baseline CT will not be exclusionary.
* Patients for whom informed consent cannot be obtained.
C: Inclusion Criteria

* Age: 18 through 82 years (i.e., candidates must have had their 18th birthday, but not had their 83rd birthday)
* Initiation of intravenous rt-PA within 3 hours of onset of stroke symptoms. Time of onset is defined as the last time when the subject was witnessed to be at baseline (i.e., subjects who have stroke symptoms upon awakening will be considered to have their onset at beginning of sleep)
* An NIHSSS \>/= 10 at the time that intravenous rt-PA is begun or an NIHSSS \>7 and \<10 with an occlusion seen in M1, ICA or basilar artery on CTA at institutions where baseline CTA imaging is standard of care for acute stroke patients.
* Investigator verification that the subject has received/ is receiving the correct IV rt-PA dose for the estimated weight prior to randomization

Exclusion Criteria

* History of stroke in the past 3 months
* Previous intra-cranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arteriovenous malformation
* Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT scan is normal
* Hypertension at time of treatment; systolic BP \> 185 or diastolic \> 110 mm Hg) or aggressive measures to lower BP to below these limits are needed.
* Presumed septic embolus, or suspicion of bacterial endocarditis
* Presumed pericarditis, including pericarditis after acute MI
* Suspicion of aortic dissection
* Recent (within 30 days) surgery or biopsy of parenchymal organ
* Recent (within 30 days) trauma, with internal injuries or ulcerative wounds
* Recent (within 90 days) severe head trauma or head trauma with loss of consciousness
* Any active or recent (within 30 days) hemorrhage
* Pts with known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency or oral anticoagulant therapy require coagulation labs results prior to enrollment. Any subject with INR \> 1.7 or institutionally equivalent prothrombin time is excluded. Patients without history or suspicion of coagulopathy do not require INR or prothrombin time lab results to be available prior to enrollment.
* Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission
* Baseline lab values: glucose \< 50 mg/dl or \> 400 mg/dl, platelets \<100,000, or Hct \<25
* Requires hemodialysis or peritoneal dialysis, or has a contraindication to an angiogram for whatever reason
* Received heparin or a direct thrombin inhibitor (Angiomax, argatroban, Refludan, Pradaxa) within 48 hours must have a normal partial thromboplastin time (PTT) to be eligible
* History of an arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days
* History of seizure at onset of stroke
* History of a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mRS score at baseline must be \< 2. This excludes patients who live in a nursing home or who are not fully independent for activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.)
* Other serious, advanced, or terminal illness
* Any other condition that the investigator feels would pose a significant hazard to the subject if Activase (Alteplase) therapy is initiated
* Current participation in another research drug treatment protocol
* Informed consent is not or cannot be obtained.
* High density lesion consistent with hemorrhage of any degree on baseline imaging
* Significant mass effect with midline shift on baseline imaging
* Large (\>1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT scan. (ASPECTS of \< 4 can be used as a guideline) Sulcal effacement and/or loss of grey-white differentiation are not contraindications to tx
* CT evidence of intrapararenchymal tumor
* Baseline CTA without evidence of arterial occlusion
D: Inclusion Criteria:Subjects will be eligible if the following criteria are met:

* Ability to provide written informed consent and comply with study assessments for the full duration of the study.
* Age \> 18 years
* NIHSS ≥ 4 or isolated aphasia or isolated hemianopsia

Exclusion Criteria:

* NIHSS \>30
* Coma
* Rapidly improving symptoms
* History of stroke in the last 6 weeks
* Seizure at onset
* Subarachnoid Hemorrhage (SAH ) or suspected SAH
* Any history of Intracrannial Hemorrhage (ICH)
* Neoplasm
* Septic embolism
* Surgery, biopsy, trauma or LP in last 30 days
* Head trauma in the last 90 days
* Bleeding diathesis, or INR \>1.7 or PTT \>1.5 times baseline or platelet \<100K
* SBP \>180 or DBP ≥100 despite treatment with 3 doses of IV Labetalol (10-20 mg Q10")
* Lacunar stroke syndrome
* CT: Hemorrhage, tumor (except small meningioma), significant mass effect, midline shift, acute hypodensity or \>1/3 MCA territory sulcal effacement
* Radiological contrast hypersensitivity
* Angiographic: Dissection, lack of access, lack of occlusion, or nonatherosclerotic arteriopathy

Answer: D