SONOlysis in Prevention of Brain Infarctions dUring Carotid Stenting and caroTid EndaRterectomy
Condition: Internal Carotid Artery Stenosis
MeSH terms: Carotid Stenosis; Brain Infarction; Infarction
Study type: Interventional
Phase: Phase 3

Summary: 
      The aim of the project is to demonstrate a fibrinolytic effect of sonothrombolysis (continual
      transcranial Doppler monitoring) using 2 MegaHertz (MHz) diagnostic probe on the reduction of
      risk of brain infarctions due to the activation of endogenous fibrinolytic system during
      carotid endarterectomy (CEA) and carotid stenting (CS). 240 patients indicated for CEA (120
      patients) and CS (120 patients) will be enrolled into the study in order to demonstrate a
      twenty-percent risk reduction of number and volume of brain infarctions detected using MRI
      examination 24 hours after CEA or CS in 5% level of significance. Patients will be randomized
      - subgroup 1 will undergo a 60minute non-diagnostic transcranial Doppler (TCD) monitoring
      during CEA or CS, subgroup 2 will undergo interventions without TCD monitoring. The second
      aim is to compare number of brain infarctions detected using MRI between CEA and CS patients.

      Confirmation of the investigators hypothesis that sonothrombolysis is able to activate
      endogenous fibrinolytic system during CEA or CS with consecutive reduction of the number and
      volume of brain infarcts, can lead to the increase of the safety of CEA and CS in patients
      with internal carotid artery stenosis. The investigators can presume that up to 50% of
      patients indicated for CEA or CS can be treated using these methods in the future.

      In the Substudy "Risk of brain infarction after carotid endarterectomy and stenting" the the
      risk of asymptomatic and symptomatic brain infarctions, changes in cognitive functions, as
      well as morbidity and mortality at 30 days between patients with symptomatic and asymptomatic
      severe internal carotid artery (ICA) stenoses undergoing elective CEA and CAS will be
      compared.

      The sample size of the Substudy was based on an expected 80% difference of new ischemic
      lesions on DWI-MRI between CEA (estimated prevalence, 30%) and CAS (54%). Pre-study
      calculations showed that a minimum of 73 patients in each group was needed to reach a
      significant difference with an alpha value of 0.05 (two-tailed) and a beta value of 0.8
      assuming that 15% of subjects would be lost to follow-up or refuse to participate in the
      study.
    

Detailed description: 
      AIM OF THE PROJECT AND HYPOTHESIS The aim of the project is to demonstrate an effect of
      continual TCD monitoring using 2 MHz diagnostic probe with maximal diagnostic energy on the
      reduction of risk of brain microinfarctions due to the activation of endogenous fibrinolytic
      system during CEA and CS. The second aim of the study is to compare the risk of brain
      infarction between CEA and CS.

      240 patients indicated for CEA (120 patients) and CS (120 patients) will be enrolled into the
      study in order to demonstrate a twenty-percent risk reduction of number and volume of brain
      infarctions detected using MRI examination 24 hours after CEA or CS in 5% level of
      statistical significance. Patients will be randomized into 2 subgroups. Subgroup 1 will
      undergo a 60minute non-diagnostic TCD monitoring during CEA or CS. Subgroup 2 will undergo
      CEA or CS without TCD monitoring. The second aim is to compare number and volume of brain
      infarctions detected using MRI between CEA and CS patients.

      Substudy "Risk of brain infarction after carotid endarterectomy and stenting" The aim of the
      prospective, randomized study was to compare the risk of asymptomatic and symptomatic brain
      infarctions, changes in cognitive functions, as well as morbidity and mortality at 30 days
      between patients with symptomatic and asymptomatic severe ICA stenoses undergoing elective
      CEA and CS.

      PATIENTS AND METHODS 240 patients with ICA stenosis indicated for CEA or CS according to the
      criteria of the American Heart Association will be enrolled into the study during a 4-year
      period. Altogether 120 patients indicated for CEA and 120 patients indicated for CS will be
      randomized for standard CEA / CS and TCD monitored CEA / CS.

      Randomization: Randomization using computer generated random allocation will be used,
      separately for CEA and CS patients.

      Substudy "Risk of brain infarction after carotid endarterectomy and stenting" Minimally146
      patients with ICA stenosis >70% (symptomatic or asymptomatic) detected by duplex sonography
      and confirmed using computed tomography angiography (CTA); indication for carotid
      intervention (CEA or CAS) according to criteria set by the American Heart Association5; age
      40-80 years; (iv) functionally independent (modified Rankin score 0-2 points); no
      contraindication to magnetic resonance imaging (MRI), computer tomography angiography (CTA)
      or digital angiography (DSA) will be enrolled to the Substudy.

      Randomization: Randomization using computer generated random allocation to CEA or CS will be
      used.

      Sonothrombolysis: In patients randomized into sonothrombolysis subgroup, middle cerebral
      artery (MCA) segment in depth 55 mm will be monitored for 40 minutes using a diagnostic 2 MHz
      probe with maximal diagnostic energy. Non-diagnostic TCD monitoring will be performed without
      detection of microembolic signals or detection of changes in blood flow. The second (control)
      subgroup will undergo a standard CEA or CS without sonothrombolysis.

      MRI protocol will consists of 4 sequences: 1. Localizer; 2. T2-weighted images (T2TSE); 3.
      fluid-attenuated inversion recovery (FLAIR); 4. diffusion-weighted imaging (DWI). Sequences
      1-3 will be applied in the same level, they will have the same slice thickness and the same
      cut number. The slice thickness comprises its own cut thickness (5 mm) + distant factor
      (30%). Standard number of slices is 19. Standard slice level is considered to be a modified
      level of skull base due to the minimalization of distant artifacts echo planar imaging (EPI)
      sequence. Sequence called "trace" with three types of magnetic resonance pictures in every
      slice: (a) T2*EPI b=0; (b) DWI b=500; (c) DWI b=1000. The fourth type of images automatically
      created an apparent diffusion coefficient (ADC) map (in-line postprocessing). DWI show a
      middle (average) diffusivity of every point of examined brain tissue when b value is 500 and
      1000. This sequence is applied in order to assess hemorrhage (T2*EPI) and monitor sites of
      reduced diffusion (DWI, b=500 and 1000). New infarctions will be evaluated only in the
      territory of treated ICA.

      Adverse effects: All adverse effects during 1 month after ultrasound monitoring will be
      registered, especially all causes for new admissions to the hospital, worsening of
      neurological symptoms (>4 points in NIH stroke scale), brain edema, symptomatic and
      asymptomatic intracranial bleeding detected in control brain MRI.

      Statistic evaluation: All statistical tests will be performed at the Department of
      Biophysics, Informatics and Biometry, Palacký University Medical School, Olomouc. Statistical
      evaluation in 5% level of significance of differences in the number and volume of brain
      infarctions detected using MRI between patients with TCD monitoring and without TCD
      monitoring during CEA or CS will be performed using Student T-test, χ2-test, Mann-Whitney
      U-test, ANOVA and multivariate analysis. Differences in the number and volume of brain
      infarctions between patients after CEA and CS will be evaluated as secondary end-points.
      Influence of other factors, e.g. age, gender, symptoms in the territory of treated artery,
      number of infarctions before CEA or CS, results of cognitive tests will be evaluated.

      Statistic evaluation for Substudy: The normality of distribution of all data will be checked
      using the Shapiro-Wilk test. Categorical variables in the two arms will be compared by
      Fisher's exact test. Continuous variables will be compared by the Student's t-test for
      normally distributed values and by Mann-Whitney U test for other values. Multiple logistic
      regression analyses were used to determine the possible predictors of a new brain infarction.
      All tests were carried out at an alpha level of significance of 0.05.

      Study protocol has been approved by the Ethics Committees in accordance with the principles
      and guidelines of the Declaration of Helsinki, 1975.
    

Intervention name(s): sonolysis; endarterectomy; carotid stenting
Intervention type(s): Procedure; Procedure; Procedure
Intervention description(s): continual transcranial Doppler monitoring with max. diagnostic intensity for 60 minutes; carotid endarterectomy; percutaneous transluminal angioplasty and stenting
Other intervention name(s): sonothrombolysis; sonothrombotripsy; carotid endarterectomy; percutaneous transluminal angioplasty and stenting
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: sonolysis; carotid; endarterectomy; stenting