Study Design

• Randomized
• Blinded
• Parallel

Patient Populations:

• Age: 18-82 years
• Initiation of IV t-PA within 3 hours of onset of stroke symptoms
• An NIHSSS ≥10 at the time that IV t-PA is begun or an NIHSSS >7 and <10 with an occlusion seen in M1, internal carotid artery, or basilar artery on CTA at institutions where baseline CTA imaging is standard of care for acute stroke patients
  
  Number of enrollees: 656
  Duration of follow-up: 90 days
  Mean patient age: 68.5 years
  Percentage female: 48%

Exclusions:

• History of stroke in the past 3 months
• Previous ICH, neoplasm, subarachnoid hemorrhage, or arteriovenous malformation
• Clinical presentation that suggests a subarachnoid hemorrhage, even if initial CT scan is normal
• Hypertension at time of treatment; systolic blood pressure >185 or diastolic >110 mm Hg or aggressive measures to lower blood pressure to below these limits are needed
• Presumed septic embolus or suspicion of bacterial endocarditis
• Presumed pericarditis including pericarditis after acute myocardial infarction
• 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
• International normalized ratio >1.7
• 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 hematocrit <25
• Hemodialysis or peritoneal dialysis, or a contraindication to an angiogram for whatever reason
• History of an arterial puncture at a noncompressible 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
• Other serious, advanced, or terminal illness
• 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 therapy
• CT evidence of intraparenchymal tumor
• Baseline CTA without evidence of arterial occlusion

Primary Endpoints:

• Rankin scale score ≤2 at 90 days

Secondary Endpoints:

• All-cause mortality
• Symptomatic ICH

Drug/Procedures Used:

Patients with a high National Institutes of Health Stroke Scale (NIHSS) score were randomized in 2:1 ratio to either endovascular therapy + IV t-PA or t-PA alone. All patients received IV t-PA (0.9 mg/kg; max 90 mg); 10% was administered as a bolus and the rest as an infusion over 1 hour. Patients in the t-PA only arm received the full dose. Patients in the endovascular arm received two thirds of the IV t-PA dose, followed by emergent angiography within 40 minutes of initiation of infusion. Midway through the trial, the safety of intra-arterial t-PA in addition to full-dose IV t-PA was established, and thus, this was incorporated into the endovascular arm after July 2011.

In the endovascular arm, no additional treatment was performed if no treatable obstruction was visible angiographically. Among those with a treatable obstruction, the choice of endovascular therapy depended on the site neurointerventionalist: thrombectomy with the Merci retriever, Penumbra system, or Solitaire FR revascularization device; or endovascular delivery of intra-arterial t-PA by means of a microcatheter. Heparin was the choice of anticoagulant for endovascular procedures (2000 U bolus, 450 U/hr infusion).

Concomitant Medications:

Antiplatelet agents (45%), statin (36%)