Advanced Image Supported Left Ventricular Lead Placement in Cardiac Resynchronization Therapy
(ADVISE-CRT II trial)

Chronic heart failure is a major cause of morbidity and mortality in the
Netherlands. Heart failure accompanied by ventricular dyssynchrony, determined
by a wide QRS complex on het electrocardiogram (ECG), is a predictor for worse
prognosis. A wide QRS complex (>120ms) is present in about 25-50% of patients
with chronic heart failure.

Cardiac resynchronization therapy (CRT) is an important therapy for patients
with dyssynchronized heart failure (ventricular dyssynchrony). With a CRT
device, a special pacemaker, the heart can be electrically stimulated (via 3
pacemaker leads in the heart) in order to achieve synchronized contraction once
more. Unfortunately up to 30-40% of patients do not benefit from CRT.
Suboptimal (left ventricular) lead positions are an imporant determinant for
CRT non-response.

To place the CRT device the implanting cardiologist currently uses fluoroscopic
projections (2D X-ray images) of the heart. With this approach, the optimal
pacing site for the pacemaker leads, unfortunately, is not visible. For
example, the pacemaker leads can not be placed to close to scarred myocardium
since this can result in detrimental effects of the treatment. On the other
hand, the left ventricular pacemaker leads should be placed in the latest
mechanically activated region.

With a new techniqe we can merge MRI images of the heart (on which myocardial
scar tissue and mechanical contraction timing can be identified) with the
fluoroscopic 2D-projection made standard during CRT implantation. In order to
achieve this fusion we need to perform an additional 3D-Xray scan of the heart
(duration approximately 5 seconds). This 3D-Xray scan increases the total
radiation exposure of the CRT implantation. Still, this technique potentially
allows the physician to perform the therapy much more accurate than before at
the optimal pacing location in the heart. Using this patient tailored approach
we believe that response to CRT can be augmented. Previous research already
demonstrated that targeted therapy (away from scar and toward the latest
mechanical contraction) improves patients' symptoms and prognosis.

We have recently demonstrated in a small pilot study that using the CARTBox
software, developed by CART-Tech B.V., the optimal location for LV lead
delivery can be visualized during CRT implantation (METC number 16/242). The
small sample size and study design however prevents us from drawing conclusion
about the efficacy, safety and feasibiliy of real-time image-guided CRT
implantations. Hence, as a next step, we want toinvestigate in a larger number
of patients the feasibility, safety and efficacy of CRT implantations guided by
CARTBox compared to standard CRT implantations.

To determine the safety, feasibility and efficacy of targeted left ventricular
lead placement with CRT procedures, using the CARTBox software.

Open interventional multi-center study with 30 prospectively included patients

Before CRT implantation, standard/routine cardiac MRI and echocardiography will
be acquired. For the present study, MRI imaged will be analyzed with dedicated
software. In this way, a 3D-MRI treatment file will be acquired using the
CARTBox software. This 3D-treatment file will be fused with live fluoroscopic
projections during CRT implantations. Fluoroscopic projections are routine for
CRT implantation procedures, yet, in order to be able to fuse the 3D-treatment
file with the fluoroscopic projections, an additional 3D-fluoroscopy scan is
performed for the study.
With this approach, the CRT device can be targeted towards the pre-precedurally
defined (via MRI) optimal pacing site. 6 months after implantation, patients
will undergo a cardiac ultrasound to determine echocardiographic response to
CRT. This is part of routine care in patients undergoing CRT, however, the
follow-up echocardiography needs to take place in the implanting center.

CRT procedure (conventional), but carried out under guidance of CARTBox
software (new)

All patients will undergo an MRI scan. In rare cases (<1/1000) an allergic
reaction can occur, such as an itch, nausea or small bumps on the skin. In the
vast majority of cases these symptoms pass quickly. In extremely rare cases
acute allergic reactions can occur, usually in subjects with known contrast
allergies. Therefore, these subjects are excluded from participation in this
study.
Recently nephrogenic systemic fibrosis (NFS) has been linked to administration
of gadolinium-based contrast agents in subjects with renal failure. Therefore,
subjects with renal failure are excluded from an MRI scan. No cases of NFS have
been documented in patients without renal failure. The benefit of the Cardiac
MRI is the knowledge of scar tissue, detailed description of LV function, and
visualization of the LV region with late contraction where the LV lead has to
be placed. For the patient, the additional burden of the MRI is the extra visit
to the hospital and claustrophobic patients may not be able to undergo the
assessment.


The risk and/or complications of the CRT implantation itself are not additional
to the study, as the CRT implantation with a quadripolar lead is a standard
procedure in the UMC Utrecht. Cardiac MRI scan will be performed before CRT
implantation.

During implantation a 3D fluoroscopy rotational scan is made. This is currently
necessary to perform fusion of the MRI scan with fluoroscopy. In the ADVISE-I
pilot study we measured there is an average 12% increase in radiation burden
using the 3D rotational scan during CRT implantation. Detrimental effects of
radiation, occur at a dose area product larger than 40 000 cGy/cm2. Whereas the
threshold dose for skin erythema is 20 000 cGy/cm2. However in the ADVISE-I
pilot study the total radiation dose remained well below these thresholds.

Importantly, because we want to get rid of the 12% additional radiation burden,
we will test (see secondary objectives) if a new developed registration method
based on 2D images instead of 3D images can replace the 3D rotational scan .
For this reason we have developed a 2D registration method for fusing MRI with
fluoroscopy. In the present study we will validate the performance of 2D
registration with respect to 3D-rotational scan based registration in the first
5 patients. If this is successful we can use the 2D registration in the last 25
patients, this will omit the 3D rotational scan and 12% additional radiation
burden in these patients. The total radiation burden will then likely be less
compared to a normal/conventional CRT implantation.

The study can increase the response of patients to CRT. By fusing MRI images
with fluoroscopy during LV lead positioning, the implanting physician can
choose the most optimal position (out of scar and towards delayed contraction)
for implanting the CRT device. A lead position away from the infarct area, and
closest to or in the latest activated area will improve LV pump function. An
improved response to CRT can improve quality of life and prognosis of heart
failure patients. Especially patients with myocardial infarction and/or
coronary artery stenosis (ischemic cardiomyopathy), since these patients are
more often non-responders to CRT.

The study may also improve the procedure itself. With increased knowledge of an
optimal lead position during implantation, future procedures can be conducted
more easily. The implanting physician can choose a target vessel for optimal
lead position. It can therefore shorten the procedure and prevent potential
complications of prolonged procedures.