The Value of CT-FFR Compared to CCTA or CCTA and Stress MPI in Low to Intermediate Risk ED Patients With Toshiba CT-FFR

Background:

Coronary Computed Tomography Angiogram (CCTA) is a non-invasive imaging modality that has
high sensitivity and negative predictive value for the detection of coronary artery disease
(CAD). The main limitations of CCTA are its poor specificity and positive predictive value,
as well as its inherent lack of physiologically relevant data on hemodynamic significance of
coronary stenosis, a data that is provided either by non-invasive stress tests such as
myocardial perfusion imaging (MPI) or invasively by measurement of the Fractional Flow
Reserve (FFR). Recent advances in computational fluid dynamic techniques applied to standard
CCTA are now emerging as powerful tools for virtual measurement of FFR from CCTA imaging
(CT-FFR). These techniques correlate well with invasively measured FFR [1-4]. The primary
purpose of this study is to evaluate the incremental benefit CT-FFR as compared to CCTA in
triaging chest pain patients in ED settings who are found to have obstructive CAD upon CCTA
(generally > 30% and < 90% stenosis). Invasive FFR and short term clinical outcomes (90 days)
will be correlated with each diagnostic modality in order to evaluate positive and negative
predictive value of each when used incrementally with CCTA.

Investigational Agent:

CCTA is increasingly becoming a preferred non-invasive imaging modality because of its high
sensitivity and negative predictive value for the detection of CAD. It has been shown to be a
robust imaging modality for evaluation of chest pain, and is associated with decreased
unnecessary hospital admission, length of stay, major adverse cardiovascular event rates,
recidivism rates, and downstream resource utilization compared to standard evaluation [5].
While findings so far are highly suggestive of CCTA's significance as a gatekeeper for ICA by
ruling out obstructive CAD, fewer than half of obstructive stenosis identified by CCTA are
ischemia-causing, signifying its poor positive predictive value and inherent lack of
physiological information [6-8]. Consequently, utilization of CCTA has not entirely averted
need for downstream testing for functional assessment of CCTA-detected obstructive lesions
either by stress testing or ICA. Recently a major treatment modality, associated with the use
of CCTA, has become available that offers promise for improving positive predictive value and
physiological relevant hemodynamic data. Advances in computational fluid dynamic techniques
applied to standard CCTA are now emerging as a powerful tool for virtual measurement of FFR
from CCTA imaging (CT-FFR). This technique correlates well with invasively measured FFR
[1-4]. While HeartFlow, Inc. has established an FDA approved process to assess coronary
artery flow using noninvasive CT-FFR, this data requires 24 to 48 hours for processing.

Toshiba CT-FFR processing is non-FDA approved. The analytic method for vessel evaluation
differs from that used by HeartFlow. Currently Toshiba is operating studies at four
organizations around the world to assess the product's performance. Recently, the company
published results from a study conducted Australia that showed positive findings on a sample
of 42 patients, with positive predictive value of 74% vs. 60%.[9] The technology was
presented at European Society of Cardiology (ESC) by Dr. S. Seneviratne and at Radiological
Society of North America (RSNA) and the American Heart Association (AHA). Using the
technology for ED patients offers potential advantage over the HeartFlow process, because the
turnaround time for the procedure is one to three hours. However, the early positive findings
need to be validated with a more robust study.

Preclinical Data:

While few publications regarding the use of CT-FFR specifically address the cost of
diagnostic work-up for obstructive disease, it is clear that the cost structure resulting
from changes in diagnostic testing will also change. Deferral or avoidance of cardiac
catheterization and nuclear stress testing will likely yield significant reductions in the
cost of the diagnostic testing. In addition, because the results of the CT-FFR are available
in the ED, CT-FFR has the potential to offer financial savings from reduced length of stay,
while increasing patient satisfaction and reducing exposure to increased risk related to the
emergency department environment.

Clinical Data to Date:

From 1/1/2009 to 3/31/2015 the investigative team introduced and operated a CCTA Chest Pain
triage program for low to intermediate risk patients at Stony Brook University Hospital ED
and non-emergency outpatient services, the only tertiary care hospital in Suffolk County, New
York (NY). Concurrently, the investigators established a registry to monitor patient outcomes
for all patients receiving CCTA at Stony Brook Medicine. The registry contained nearly 15,000
patient CCTA procedures. The major registry study established the effectiveness of CCTA as an
imaging modality for evaluating ED chest pain in a cost efficient manner with a false
negative rate less than 1% [5]. However, the registry reflects the poorer positive predictive
values documented by other industry studies [6-8].

False positive workup results in the necessity of performing cardiac catheterization on
patients at risk for obstructive disease based on assessment with current standard of care
(combined screening with CCTA and stress MPI). Reduction in the rate of false positive
testing would lead to reduction in risk from invasive procedures and radiation exposure to
patients and reduced cost to the health care system.

Study Objectives:

The purpose of this study is to evaluate the incremental benefit of Fractional Flow Reserve
derived from CCTA (FFR-CT) compared to invasive FFR as the gold standard for patients with
obstructive disease (generally, >= 30% stenosis).

General Study Design:

This will be a prospective clinical trial designed to evaluate the incremental benefit of
virtual FFR measured from CCTA, compared to invasive FFR and CCTA alone for the detection of
flow-limiting coronary stenosis, as defined by invasive FFR <=0.8 and vessel diameter of
>=2mm.

1,142 consecutive patients who present to North Shore University Hospital Emergency
Department (ED) for CCTA due to chest pain or angina over a two year period and meeting the
study inclusion criteria are eligible for the study (Figure 1). The investigators will employ
CCTA-appropriateness criteria to ensure proper selection of patients, derived from the
Appropriate Use Criteria for Cardiac Computed Tomography published in 2010 and jointly
authored by multiple societies including American College of Cardiology Foundation (ACCF),
Society of Cardiovascular Computed Tomography (SCCT), and American College of Radiology (ACR)
[11]. FFR-CT measurements will be performed following CCTA scan acquisition on software
developed by Toshiba America Medical Systems, Inc. All eligible patients will undergo
320-slice multi detector CCTA and CT-FFR measurements. The severity of the stenosis will be
determined on site by level III CCTA readers.

Patients with borderline (50% - 70%) or positive CCTA (>70%) stenosis readings will undergo
ICA with invasive FFR measurement in accordance with accepted guidelines and established
practice standard. Those patients with invasively measured FFR<=0.8 and with vessel diameter
of >= 2mm, or those who require revascularizations based on invasively estimated stenosis
severity (for patients who are totally obstructed) will be considered to have flow-limiting
obstructive CAD, while the rest will be considered to have non-flow limiting obstructive CAD
(if also >50% stenosis on ICA). If stenosis severity turns out to be < 50% after ICA, these
patients will have been shown to have non-obstructive CAD. (Figure 1). Patients with 30% to
49% obstructive stenosis by CCTA standards and with positive CT-FFR, will also undergo
invasive FFR and follow the protocol for those with > 50% obstruction. Patients with 0 to 49%
obstructive disease and negative CT-FFR will be referred to optimal follow up care only.

Inclusion Criteria:

1. Capable of giving informed consent.

2. Able to cooperate with the technician performing the procedure.

3. Patient must have Body Mass Index (BMI) <= 50.

4. Patients must have non-ST Elevation Myocardial Infarction (STEMI) Electrocardiogram
(EKG) without acute changes.

5. Patients must present to North Shore University Hospital ED with Acute Chest Pain and
require evaluation of coronary stenosis for the provisional diagnoses of acute chest
pain or unstable angina or angina equivalent, and meet the criteria for CCTA by Heart
Score Triage for the purpose of evaluation coronary stenosis for the provisional
diagnoses of chest pain or angina or angina equivalent.

7.Patients must be able to take nitroglycerin and beta blockers. - 8.Patients must be 18
years of age or older.

Exclusion Criteria:

1. Patients must not have a history of coronary stenting or coronary artery bypass graft.

2. Patients must not have severe or end stage renal disease as diagnosed as estimated
glomerular filtration rate (eGFR)<50.

3. Patients must not have a BMI>50.

4. Patient must not have any allergies to contrast.