Mild Acute Ischemic Stroke With Large Vessel Occlusion (MISTWAVE)
Mild Acute Ischemic Stroke With Large Vessel Occlusion (MISTWAVE)
Stroke remains the leading cause of disability in the United States. An estimated 40-50% of
 all ischemic strokes are caused by large-vessel occlusion of a major cerebral artery (LVO).
 However, in some cases, the occlusion results in mild symptoms, at least initially, and these
 patients frequently do not receive any treatment. These strokes, however, may result in
 unfavorable long-term outcomes despite relatively benign initial course. Recent large
 randomized studies in patients with severe stroke symptoms and associated LVO showed efficacy
 and safety of endovascular mechanical thrombectomy, but patients with mild symptoms were not
 specifically addressed.

 Based on the investigators' own data and limited evidence in the literature, the
 investigators propose that early mechanical thrombectomy in patients with LVO associated with
 mild stroke symptoms (defined as NIHSS ≤ 5) is safe, and results in favorable long-term
 patient outcomes.

 The objective of this prospective pilot study is to assess the safety and outcomes of
 mechanical thrombectomy in patients presenting with acute ischemic stroke due to a large
 vessel occlusion in the anterior or posterior circulation under 24 hours with mild symptoms
 (NIHSS ≤ 5).
Patients who present with mild stroke symptoms (mAIS), and are also found to have an
 intracranial large vessel occlusion (LVO) pose an exceptionally difficult therapeutic
 dilemma. The need for any acute treatment is often debated since these patients "only" have
 mild deficits, and any therapy has associated risks. However, it has been shown that acute
 ischemic stroke (AIS) can lead to considerable morbidity and mortality even in patients
 presenting with mild symptoms (mAIS) in the presence of LVO. Despite reports that such
 patients have less favorable outcomes, these patients are often excluded from acute stroke
 therapy. Recent studies demonstrated that, despite mild and rapidly improving symptoms, many
 patients end up with unfavorable outcome. While the most recent AHA/ASA guidelines no longer
 recommend excluding patients with milder improving symptoms from intravenous tissue
 plasminogen activator administration, the role of endovascular intervention has not been
 clarified for these patients.

 Prior data has shown high morbidity and mortality in mAIS patients (without specified large
 vessel status), who did not receive IV tPA, demonstrating that as high as 32% of patients was
 dependent during discharge or died in one study. A common reason for foregoing treatment in
 this patient group was that mild symptoms or rapid improvement were a contraindication to
 IV-tPA administration according to previous ASA/AHA guidelines. Higher morbidity was
 specifically noted in patients with concurrent large vessel occlusion as a cause of the
 symptom in another study. Mokin et al showed that for LVO patients excluded from
 thrombolysis, only 2/3rd could walk independently at discharge.

 When assessing predictors of poor outcome, LVO seems to correlate with poor outcome despite
 mild symptoms. Nedeltchev et al published a study with 162 patients with either mild stroke
 symptoms (NIHSS of 3 or less) or rapidly improving symptoms (NIHSS improvement of 4 points or
 more), in which 25% of the patients had an unfavorable outcome. NIHSS of 10 or more and
 proximal vessel occlusion were independent predictors of poor outcome. LVO in patients with
 rapidly improving /mild symptoms conferred an 18-fold increased risk of early neurological
 deficit with infarct expansion. Patients with LVO were also more likely to have increased
 modified ranking scale (mRS), and LVO was an independent predictor of decline in functional
 status and a borderline significant predictor of poor outcome when adjusting for age, gender
 and presenting NIHSS.

 NIH Stroke Scale Score Threshold The ideal NIHSS cutoff value for "mild" stroke remains
 unclear, and varies across studies. The investigators specifically chose the NIHSS 5 cut-off
 value for the cohort after careful consideration of the results of several earlier reports,
 which were available at the initiation of our research project. These studies, albeit with
 limited sensitivity and specificity, have concluded that an NIHSS cut-off of 7-10 and higher
 might be a reliable predictor of LVO. Since the investigators were trying to capture a
 controversial stroke population that was unlikely to have LVO because of mild symptoms, the
 investigators decided to include patients with NIHSS 5 or less.

 Currently approved treatment and limitations At present, the American Heart Association and
 American Stroke Association guidelines recommend that eligible ischemic strokes be treated
 with IV tissue plasminogen activator (tPA) and/or mechanical thrombectomy. Severity of the
 stroke is based on the National institute of health stroke scale (NIHSS), and the guidelines
 do not specify any thrombolysis treatment for mild strokes.

 Mechanical thrombectomy using stent retrievers for LVO stroke has become the standard of
 care; however, current guidelines exclude patients with mild or improving symptoms. These
 recommendations were made based on the 2015 randomized control trials, most of which did not
 include patients with NIHSS <6.

 Despite the MR-CLEAN trial's inclusion of patients with NIHSS as low as 2, which showed
 efficacy of IAT for LVO, it is unclear what proportion of successfully treated patients were
 actually in the mAIS category. The PRISMS study investigated the efficacy IV-tPA in mAIS
 patients, although establishment of large vessel status was not specifically required
 (NCT02072226). The TEMPO -1 trial showed safety and feasibility of tenecteplase in patients
 with LVO and mAIS, and the TEMPO - 2 trial (NCT02398656) comparing tenecteplase to standard
 therapy is currently ongoing.

 The recently completed DAWN trial is an international multi-center randomized trial study of
 patients with acute ischemic anterior stroke due to large vessel occlusions between 6 -24
 hours of stroke with endovascular therapy. The results from 206 patients enrolled in the
 trial demonstrated treatment with use of stentriver significantly decreased post-stroke
 disability and improved functional independence at 90 days when compared to medical
 management alone (48.6% vs 13.1%, p<0.001), a relative reduction in disability of 73%
 percent. The study showed that one in 2.8 patients treated with the stentriever within 24
 hours of a stroke is saved from severe disability. Another large trial, the Diffusion and
 Perfusion Imaging Evaluation for Understanding Stroke Evolution 3 (DEFUSE 3), was halted
 after the DAWN trial results were presented. This study enrolled patients with large vessel
 occlusion presenting within 6 and 16 hours of stroke onset based on advanced imaging
 criteria. Patients who underwent endovascular therapy had 2.77 times greater odds of
 regaining functional independence at 90 days, versus medical management alone (45% vs 17%,
 p<0.001), showing benefit for the endovascular group.

 Acute vertebrobasilar occlusion The efficacy of mechanical thrombectomy in the anterior
 circulation raised the question of its potential applicability in the posterior circulation.
 Acute basilar occlusion accounts for approximately 1% of all acute ischemic strokes, and is
 disproportionately associated with a mortality rate of approximately 70%. Given these
 statistics, procedural risks in acute basilar occlusion syndromes have long been regarded
 much lower than the risk of unfavorable outcome without intervention. Therefore these
 patients have largely been omitted from clinical trials resulting in a paucity of clinical
 evidence, in contrast with anterior circulation strokes. Patients with mild-to-moderate
 posterior circulation AIS pose a unique challenge, as retrospective data correlate the
 patients' clinical outcome with severity at presentation, giving them up to 67% chance of
 achieving a favorable outcome.
Inclusion Criteria:

 1. Age 18 - 85.

 2. Clinical signs consistent with acute ischemic stroke.

 3. No prestroke functional dependence (prestroke Modified Rankin Score ≤ 1).

 4. NIHSS <6 at the time of enrollment.

 5. Consent obtained within 24 hours from last known well.

 6. Thrombolysis in Cerebral Infarction (TICI) 0-1 flow in

 1. The M1 or M2 segment of the MCA, or carotid terminus confirmed by CT or MR
 angiography; or

 2. The basilar artery.

 7. Subject can be treated within 1 hours (60 minutes) from pre-procedure CT or MRI to
 groin puncture.

 8. CT or MRI-DWI ASPECT Score of > 6 in the anterior circulation, or posterior
 circulation ASPECT Score (pc-ASPECTS) of > 7.36

 9. Subject is willing to conduct protocol-required follow-up visits.

 10. Subject or subject's legally authorized representative has signed and dated an
 Informed Consent Form.

 NB: Patient can be enrolled regardless of whether the patient received IV t-PA. However,
 the decision for administration of IV t-PA must be made before enrolling into the study.

 Exclusion Criteria:

 1. Female who is pregnant or lactating or has a positive pregnancy test at time of
 admission.

 2. Known serious sensitivity to radiographic contrast agents.

 3. Subject with a pre-existing neurological or psychiatric disease that would confound
 the neurological and functional evaluations. Computed tomography (CT) or Magnetic
 Resonance Imaging (MRI) evidence of hemorrhage on presentation.

 4. CT or MRI ASPECT score of ≤6 in the anterior circulation, or pc-ASPECTS of ≤7.

 5. CT or MRI evidence of mass effect or intra-cranial tumor (except small meningioma).

 6. Current participation in another investigation drug or device treatment study.

 7. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency.

 8. Warfarin therapy with INR greater than 1.7.

 9. Low molecular Weight Heparins, Heparin, Factor Xa inhibitors or direct thrombin
 inhibitors as full dose within the last 48 hours from screening and must have a normal
 partial thromboplastin time (PTT) to be eligible.

 10. Baseline lab values: glucose < 50 mg/dL or > 400 mg/dL, platelets < 100,000 or Hct <
 25.

 11. Renal Failure as defined by a serum creatinine > 2.0 or Glomerular Filtration Rate
 [GFR]< 30.

 12. Life expectancy of less than 90 days.

 13. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI
 scan is normal.

 14. Presumed septic embolus, or suspicion of bacterial endocarditis.

 15. Preprocedural or intraprocedural diagnosis of an unexpected vascular lesion or
 condition that may require additional, non-standard thrombectomy endovascular
 procedure(s), such as stenting, angioplasty or other treatment, and pose an additional
 or elevated risk. Such conditions, listed below, exclude or invalidate enrollment in
 the study:

 1. Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, cerebral
 aneurysm, or arteriovenous malformation

 2. Previously unknown dissection, vasculitis, vasculopathy, severe hemodynamically
 significant vascular stenosis, or other atypical vascular lesion

 3. Tandem lesions, defined as an occlusion involving both the cervical and
 intracranial segment of the same vascular distribution

 4. Stroke or vascular occlusions in multiple vascular territories