MRI Investigation in Transcatheter Aortic Valve replacement with Claret: a randomized study to assess by MRI the reduction in cerebral embolic lesions during Transcatheter Aortic Valve Replacement with the Claret embolic protection device

Symptomatic severe Aortic Valve Stenosis (AS) has a dismal prognosis. Surgical
Aortic Valve Replacement (SAVR) is the standard treatment of care[1-2]. The
first Transcatheter Aortic Valve Implantation (TAVI) to treat severe AS was
performed in 2002[3]. Since its introduction the technology has progressed
through several device and procedure iterations with a current worldwide TAVI
experience exceeding 50000 cases. The TAVI technology is reserved for patients
with severe AS and a (very) high operative risk. Both surgical and catheter
based therapies can be complicated by cerebrovascular events [4]. These
cerebrovascular events often have an embolic origin. The embolic nature can be
variable (cholesterol particles, air, atherosclerotique plaque material,
thrombus, calcified valve material). The incidence of clinical stroke after
SAVR and TAVI varies between 2 and 10%[5-8].

Cerebral infarctions can be identified by Computed Tomography (CT), although
the smaller (and often clinically silent) ischemic lesions remain undiagnosed.
Conventional Magnetic Resonance Imaging (MRI) outperforms CT in its ability to
identifiy new cerebral lesions.. Even subclinical subtle ischemic changes can
be demonstrated by MRI. MRI studies following cardiac surgery have demonstrated
the occurrence of new ischemic cerebral lesions in 0-58% [9-11]. The impact of
these new ischemic cerebral lesions after surgery on neurocognitive function is
controversial
[12-13]. The variability in frequency and at first glance conflicting results
can be explained by 1) timing of MRI following surgery, 2) the fact that these
(subclinical) new lesions may be transient and 3) the limitations of MRI in
detecting small ischemic lesions.
Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) is a relatively new MRI
technique capable of detecting small ischemic lesions in the brain within small
time intervals following the ischemic insult. DW-MRI measures microscopic
motion of water molecules in the brain. Ischemic areas are characterized by
impaired diffusion, which is visible as regions with high density by DW-MRI.
Diffusion images of the brain can identify (sub)acute ischemic lesions with
very high sensitivity and specificity. This MRI sequence has already proven its
performance in the evaluation of ischemic brain lesion during carotid
endarterectomy and carotid stenting [14-17].


New cerebral lesions by DW MRI are reported in 48% of patients after valve
surgery and in up to 70 - 80% after TAVI [18-19]. Most of these lesions have no
immediate clinical consequences but neurocognitive decline in the long term
remains to be investigated. Several studies have linked (initially subclinical)
micro-emboli after heart surgery to neurocognitive outcome [20-21]. Vascular
cognitive impairment (VCI) could also result from multiple initially
subclinical cerebral embolisations.

Embolic Protection Devices (EPD) are endovascular devices aiming to prevent
cerebral embolisations. These devices have proven efficacy in carotid and
saphenous vein graft stenting with clinically significant reductions in major
adverse events (mortality, stroke, myocardial infarction)[22-24].

The Claret device (Claret Inc.) is an Embolic Protection Device (EPD)
consisting of two nitinol baskets to be introduced through the right radial
artery. One basket is positioned in the brachiocephalic trunk, the other in the
left common carotid artery. The baskets consist of a mesh graft that will
capture particles and debris of at least 90um in diameter.
The device has CE mark approval for use in Transcatheter Aortic Valve
Implantation. The first-in-man experience demonstrated procedural safety.
Whether the use of the Claret device will reduce the number and extent of new
ischemic lesions by DW-MRI has not been established yet.

This is a multi center randomized study including 54 patients with aortic
stenosis scheduled for TAVI. Randomisation will be performed by sealed
envelopes.

Patients who are excluded from follow up MRI because of pacemaker issues will
continue clinical follow up per protocol. Enrollment will continue until a
total of 54 patients have an analyzable DW MRI exam within 3 days post TAVI. A
senior interventionalist at the outpatient clinic or on the ward will approach
eligible patients and ask written information. Patients will be randomized
after signing the informed consent form.

All patient data will be entered in a dedicated database. Baseline DW-MRI will
be performed within 1 week prior to the procedure. Follow up DW-MRI will be
obtained within 3 days after the procedure. During the follow up MRI exam, a
ward nurse will accompany the patient. In case of clinically significant and/or
unexpected new findings by follow up MRI, this will be communicated to the
patient by the treating physician and appropriate follow up will be organised.
A second follow up DW-MRI exam of the brain will be organized 3 months after
the TAVI procedure.

A 6F radial artery sheath is introduced using the Seldinger Technique. The
Claret device is advanced through a right radial access deploying the distal
basket in the left common carotid artery and the proximal basket in the
brachiocephalic trunk. The Claret is introduced in the catheterization lab with
the patient under general anesthesia and prior to insertion of the 18F arterial
sheath in the common femoral artery.

With an aging population the incidence of symptomatic aortic stenosis is
expected to rise. SAVR is the standard of care. The operative risk increases
with age and in up to one third of contemporary AS patients AVR is denied
because of age, comorbidities or patient preference. TAVI is an established
option in this selected patient cohort at (very) high operative risk.

The TAVI experience is rapidly mounting worldwide. DW-MRI detects subclinical
new ischemic cerebral lesions after TAVI in the majority of cases. Although the
immediate clinical impact seems negligible, the implications on the longer term
are unknown. These subclinical cerebral lesions may play a role in
neurocognitive deterioration. If the use of the Claret device in TAVI
procedures may reduce the incidence of these cerebral lesions this may have
considerable clinical significance in the long run. Patients who are
participating in this study may potentially have a significant clinical benefit.

This study may indicate whether use of the Claret device will reduce the
occurrence of new cerebral lesions and/or the extent of these lesions detected
by DW-MRI. If a clear reduction of new cerebral lesions (e.g. >25% reduction)
and/or extent of these lesions are demonstrated, the results should be
reproduced in a prospective randomized trial. This may then also assess whether
the Claret device will reduce the number of clinical ischemic strokes and
whether subclinical cerebral lesions play a role in neurocognitive function in
the longer term.

The established contraindications for MRI apply. Prolonged (>72 hours)
continuous rhythm monitoring is required in all patients. During the post
procedural MRI the monitoring will be interrupted. Therefore a nurse of the
cardiology/ ward will accompany the patient during the MRI exam.

During the introduction of the Claret device potential arterial damage and
thrombo-embolic phenomena (air, thrombus etc*) are possible. Its identification
is a secondary endpoint of this study.