IMaging Della PLAcca Carotidea
Condition: Carotid Artery Plaque; Atherosclerosis; Ischemic Stroke
MeSH terms: Ischemic Stroke; Carotid Stenosis; Atherosclerosis
Study type: Interventional
Phase: Phase 3

Summary: 
      Background-White matter hyperintensities (WMH), patchy areas of hyperintense signal on
      T2-weighted or Fluid Attenuated Inversion Recovery sequences on brain magnetic resonance
      imaging (MRI), are believed to reflect cerebral burden of ischemic damage and are associated
      to incident stroke, dementia and eventually mortality in otherwise healthy subjects. Also
      brain atrophy has been related with presence of carotid atherosclerosis and vascular
      cognitive impairment. Carotid atherosclerosis may contribute to the genesis of WMH. A recent
      meta-analysis by our group comprising 5306 subjects was able to demonstrate an association
      between the presence of carotid atherosclerosis and WMH (odds ratio, OR, 1.42, 95% confidence
      interval [CI] 1.22-1.66).

      Objective-To evaluate the relation between carotid artery plaque characteristics,
      cardiovascular risk factors and brain atrophy/WMH burden analyzed quantitatively as number
      and volume of lesions and as brain volumes, and progression over 18 months of follow up in
      subjects asymptomatic for cerebrovascular disease with a carotid artery stenosis <70%.
    

Detailed description: 
      -  Ischemic stroke and vascular cognitive impairment pose a massive clinical, social and
           economic burden. Disruption of carotid plaques, often non-obstructive, with subsequent
           thrombosis and distal embolization is one of leading pathogenetic mechanism of ischemic
           stroke. The widespread use of brain magnetic resonance imaging (MRI) has enabled an
           increased recognition, especially in elderly subjects, of cerebral alterations in
           apparently healthy individuals.

        -  Carotid plaque may be causative in the development of white matter hyperintensities
           (WMH, patchy areas of signal hyperintensity on T2-weighted and/or fluid attenuated
           inversion recovery -FLAIR- sequences), silent brain infarcts (SBI) and eventually brain
           atrophy.

        -  The hypothesis of the investigators is that carotid plaques with features of
           vulnerability detected by multimodality imaging (including standard ultrasound, contrast
           enhanced ultrasound -CEUS-, contrast enhanced CT angiography) and larger extent of
           atherosclerotic process, even if determining only an intermediate degree of stenosis,
           could bear a more rapid progression of silent WMH and brain atrophy.

        -  Carotid CT and CEUS allow fast and reproducible evaluation of plaque size and
           morphology, alongside with functional parameters. Plaque density and positive
           remodelling on CT have been repeatedly associated to histological features of plaque
           vulnerability. At the same time, when compared to standard duplex evaluation, CEUS
           allowed a better imaging definition of plaque margins and extension, and to evaluate
           intraplaque neovascularization. The latter associates with local inflammation and plaque
           vulnerability, and might give rise to plaque hematomas, which are among the substrates
           for lesion progression and for the development of atherothrombosis.

        -  In the initial phase of the study also hybrid imaging with positron tomography and
           computed tomography angiography (PET/CTA) using 11C-PK11195 was used to detect and
           quantify intraplaque inflammation in humans.(7) C-PK11195 is a selective ligand for
           translocator protein, 18kDa (TSPO), which is highly expressed on the surface of
           activated monocytes/macrophages. This part of the study was prematurely stopped due to
           problems with the production of the radiotracer with 11[C] (only 13 patients were
           studied with this approach).

      Primary endpoints:

      - The primary endpoint is to identify independent predictors (plaque-related or
      patient-related) with the progression of WMH through multivariable logistic regression
      analysis.

      Progression of WMH was considered as dichotomous variable: progression versus no progression
      of WMH.

      - The co-primary end-point is to identify independent predictors (plaque-related or
      patient-related) with the progression of gray matter (GM)/all brain atrophy through
      multivariable logistic regression analysis. Progression of brain atrophy was considered as
      dichotomous variable: progression versus no progression of GM/all brain atrophy.

      Statistical considerations:

      The investigators calculated the sample size for multivariate logistic regression analysis
      with a power of 0.8 and an alpha of 0.05. The investigators will analyze the highest tertile
      of carotid plaques burden in terms of plaque volume versus others (see Sillesen, 2012). By
      definition, the prevalence of high burden atherosclerosis will be 33%. The investigators
      estimated a clinically relevant probability of progressing in terms of WMH in the high burden
      group to be 50%, while subjects without high burden plaques are estimated to progress in
      terms of WMH as the general population with carotid atherosclerosis in a similar time frame.
      This probability would be estimated to be around 15% (see Dufoil, 2005 and Pico, 2002). The
      estimated sample size would be 58 individuals.
    

Intervention name(s): Visipaque 320 and SonoVue
Intervention type(s): Drug
Intervention description(s): Intervention is related to the administration of contrast agents:
Iodixanol, 320 mg of iodine per millilitre, Visipaque 320 (GE Healthcare, Milwaukee, WI, USA) for contrast-enahnced CTA, Sodium hexafluoride (SonoVue, Bracco Imaging, Milan, Italy) for CEUS
Other intervention name(s): Contrast agents
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Carotid atherosclerosis; Carotid plaque; Brain magnetic resonance imaging; Contrast enhanced ultrasound; Carotid CT angiography; Silent brain ischemia; Vascular cognitive impairment