The assessment of the Plaque At RISK by non-invasive (molecular) imaging and modelling (ParisK): Prospective clinical study for diagnosis efficacy for high risk plaque and stroke.

The possibility of the identification of the risk of rupture of a carotid
plaque will have tremendous impact in clinical decision making. Firstly, in
symptomatic patients with a 30-69% stenosis, who are currently not operated
upon according to the current guidelines, identification of the risk of rupture
plaque could identify patients who have a high risk of recurrent stroke, and
would, therefore, benefit of carotid intervention, such as endarterectomy or
stent placement. This could potentially prevent a substantial number of
strokes. Secondly, in all symptomatic patients with a 70-99% stenosis carotid
intervention should be considered, according to the guidelines. However, only
one out of six patients with a 70-99% stenosis benefits from a carotid
intervention. Identification of patients with a high risk of a recurrent stroke
would reduce the number of unnecessary interventions substantially (Rothwell et
al. 1999). Hence, a diagnostic imaging test with high accuracy for recurrent
stroke prediction has tremendous clinical impact in patients with carotid
artery disease.
Previous studies have evaluated the use of imaging to assess carotid plaque
vulnerability, mostly showing a good correlation between imaging and histology
and/or clinical characteristics. Plaque vulnerability is defined by a large
necrotic core, a thin fibrous cap, the presence of inflammatory cells,
intraplaque hemorrhage and/or neovascularisation (vasa vasorum). However,
previous studies have focused on single modalities (magnetic resonance imaging
[MRI], multidetector-row computed tomography [MDCT], ultrasonography [US], or
transcranial Doppler [TCD]), and have used relatively small cohorts (Altaf et
al. 2008, Takaya et al. 2006, Wintermark et al. 2008, Li et al. 2008, Underhill
et al. 2008, Cappendijk et al. 2005, Fayad et al. 2004, Yuan et al. 2002,
Henneman et al. 2008, Markus et al. 2005), This could be the reason why
carotid artery imaging studies so far have not changed the therapeutic
guidelines. In addition, the imaging modalities so far may not have delivered
the necessary sensitivity to achieve the goal of changing the guidelines.
Therefore, a clinical trial will be performed in symptomatic patients with a
30-69% stenosis (n=244) who are not scheduled for carotid intervention.
Participating patients will undergo baseline imaging, which includes 3T MRI of
the carotid atherosclerotic plaque and brain, MDCT and US of the plaque, and
TCD registration for emboli detection in the middle cerebral artery (which is a
measure of plaque thrombogenicity). At baseline, a blood sample will also be
taken to assess the presence of certain biomarkers, which may provide
additional information on plaque vulnerability (Lobbes et al. 2006). Patients
will be followed-up yearly until the end of the study. After two years all
imaging modalities will be repeated for the first 150 patients. For the
remaining patients, brain MRI will be repeated.

The main objective is to show whether imaging characteristics assessed at
baseline can predict clinical events in patients with a 30-69 % symptomatic
carotid stenosis.

Prospective study.

Participating patients will undergo an MRI, MDCT, US and TCD examination. In
addition, a blood sample will be taken for detection of biomarkers.

Burden:
-During the MRI examination, one is laying in the supine position for
approximately 10 minutes and subsequently for another 45 minutes. This does not
have to be a problem, but it can be difficult for patients with back problems.
The MRI scanner produces a lot of noise during the examination, which can be
unpleasant for the patient. Therefore, participating patients will use a
protecting head set or ear plugs. During the MRI examination, a contrast agent
will be intravenously administered. During injection, patients may experience a
cold feeling in their arm. The MRI scanner is a kind of tube, with openings in
the front and back. Still, some patients may feel uncomfortable when laying in
the tube.
-During the CT examination, one is laying in the supine position for
approximately 10 minutes. This does not have to be a problem, but it can be
difficult for patients with back problems. During the CT examination, a
contrast agent will be intravenously administered, and patients can experience
a warm feeling. The CT scanner is a kind of tube, with openings in the front
and back. Still, some patients may feel uncomfortable when laying in the tube.
-During the US examination, one is laying in the supine position on a bed for
approximately 10 minutes. Most patients experience the US examination as
comfortable. The TCD examination will take four hours. The TCD examination is
harmless. However, the mobile TCD device may cause some discomfort after a
while.
-For biomarker detection, a blood sample (30 ml) will be taken from a vein in
the arm.

Risks:
-MRI does not using ionizing radiation. However, patients with pacemakers,
metal implants, vessel clips, or metal splinters in the eye will be excluded
from this study. The side effects of the MRI contrast agent (Gadobutrol) are
rare and are amongst others nausea (0.25%), vomiting (0.05%), urticaria
(0.04%), feeling of warmth, tachycardia, wheals (for each 0.03%), dizziness,
itching, vasodilatation, itchy throat (for each 0.02%) and cough, dyspnoea,
flushing, hives, generalized itching, oral dryness, facial redness, sensation
of heat, skin disorder and aggravated nausea (for each, (0.01%). In severe
cases, an allergic reaction and shock could occur. In most cases side effects
occur immediately after contrast injection, and therefore patients will remain
in the hospital for 30 minutes after injection. The administration of the
contrast agent is relatively safe and side effects are rare. At the place of
injection of the contrast agent, (temporary) bruising or swelling may occur,
and the place may be sensitive. In rare cases, an infection could occur at this
place.
-An MDCT examination is not harmful for one*s health. However, MDCT uses
ionizing radiation: The radiation dose of an MDCT examination is approximately
2.2 mSv. The radiation dose for the perfusion CT is approximately 7.2 mSv. The
CT contrast agents (iodixanol and iopromide) are associated with a low rate of
side effects. The most reported side effects are feeling of warmth (1.3 %) and
nausea (0.3%). In severe cases, contrast-induced nefropathy could occur.
However, the use of the CT contrast agents are relatively safe and adverse
effects rarely occur. At the place of injection of the contrast agent,
(temporary) bruising or swelling may occur, and the place may be sensitive. In
rare cases, an infection could occur at this place.
-The US and TCD examinations are harmless (no associated health risks).
-Blood sampling is not dangerous and will be performed by an experienced nurse
or medical doctor. At the place of blood sampling, (temporary) bruising or
swelling may occur, and the place may be sensitive.