Mild Acute Ischemic Stroke With Large Vessel Occlusion (MISTWAVE)
Condition: Acute Ischemic Stroke
MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Ischemia
Study type: Observational

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): Mechanical Thrombectomy
Intervention type(s): Procedure
Intervention description(s): Acute Ischemic Stroke patient with Large Vessel Occlusion and NIHSS less than or equal to 5 will have a standard of care mechanical thrombectomy. Mechanical thrombectomy is a treatment for stroke that removes clots that block large blood vessels. Some patients may be candidates for this procedure using an angiogram or a catheterization and a device that grabs clots and removes them, to reestablish blood flow to the brain.
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Males and females between 18-85 that present with acute ischemic strokes with large vessel
        occlusions and NIHSS<6.
      
Keywords: Large Vessel Occlusion; mechanical thrombectomy; acute ischemic stroke