Acute Chest Pain Imaging in the ED With the Combine CCTA and CT Perfusion

BACKGROUND AND RATIONALE:

Due to the subjectivity of clinical symptoms and the indirect nature of established ischemia
tests, effective initial triage of patients in the ED with acute new onset chest pain is
difficult and leads to a high number of patients that are admitted to the hospital despite
not having obstructive coronary disease. In the subsequent work up, these patients require
extensive testing with significant resource consumption and sometimes delayed treatment. The
ability to obtain information on the presence of coronary artery stenoses and plaque early in
a noninvasive fashion could substantially enhance initial triage in the ED for these
patients.

A combined approach as proposed here using CT coronary angiography to assess the coronary
morphology together with CT myocardial perfusion assessment would address morphology and
function and help to more correctly characterize coronary lesions for decision making of a
potential coronary intervention.

Coronary CTA Analysis:

MDCT data sets are assessed qualitatively for the presence of coronary disease within all
coronary segments, including side branches. The assessment is performed on original axial
source images; thin slice (5mm) MIP's and MPR reconstructions orthogonal and perpendicular to
the vessel centerline, and short axis cross-sectional reconstructions (0.625-mm-thickness).
The analysis is performed per segment and per patient.

CT Myocardial Perfusion Analysis:

The initial evaluation of perfusion is performed by reconstruction of short axis images
viewed in thick multiplanar reformation (MPR) with slice thickness between 5mm and 10mm.
Increasing slice thickness increases the voxel size and thus decrease image noise and
improves low contrast resolution. For scans with increased image noise, a smoother
reconstruction algorithm is also useful. A true perfusion defect will persist throughout
multiple different phases and will be visualized in both systole and diastole. On the other
hand, a potential defect that is only present in one phase (i.e. only in systole) and then
disappears is likely to represent an artifact due to motion (e.g. false positive). In order
to identify regions of myocardium that have minor discrepancies in tissue density, narrow
window width is preferred, as higher contrast will be achieved. Measuring the attenuation
value on first pass computed tomography (CT) perfusion images is helpful in identifying
perfusion defects (HU ~ 50) vs. normal (remote) myocardium (Hounsfield Units (HU) ~ 100). A
17-segment model as defined by the American College of Cardiology (ACC) / American Heart
Association (AHA) is used to determine perfusion defect in a particular myocardial segment
and coronary artery distribution. A score on a scale from 0-4 is graded for each myocardial
segment depending on the extent or area of perfusion defect within the segment. The sum of
all the segment scores is used to determine if the patient has a disease (e.g., if the
maximum score attainable is 68, so any sum score > 3 correlates to a 5% volume ischemia in
the myocardium and is designated as disease at the patient level.)

- Decision to do CT myocardial Perfusion will be made by the cardiac radiologist after the
acquisition of the calcium score or after identifying a moderate stenosis or
non-evaluable segment as described in the protocol.

- The results of the coronary CT angiography and the CT myocardial Perfusion will be used
together to make the decision of whether to send the patient home or to cath. Patients
will be admitted for further cardiac investigation if: stenosis > 70% by Coronary CT
angiography or intermediate stenosis (50-70%)/non-diagnostic resting coronary CT
angiography with CT myocardial perfusion defect. Patients will be considered negative
and excluded from acute coronary syndrome if stenosis by coronary CT angiography is <
50% or an intermediate/non-diagnostic lesion is seen and no myocardial ischemia is
present by CT myocardial Perfusion.

Study Objective The main purpose of this study is to have a definite ED chest pain admission
triage, which will help to reduce the length of stay and direct patient cost. This approach
will reduce the economic burden in intermediate risk group patients as well.

Study Hypotheses

The proposed study seeks to evaluate the following hypotheses:

I- The combined evaluation of CT angiography with CT myocardial perfusion is more efficient
in correctly diagnosing the obstructive disease. This will reduce the length of hospital stay
(LOS), in the assessment of intermediate risk patients at detecting or excluding acute
coronary syndrome, in patients presenting with chest pain to ED as compared to a strategy
with SPECT alone.

II- To reduce the direct patient care costs in the same patient population. This study is
proposing a new chest pain algorithm in arm-B at West Kendall Baptist hospital (combined
approach of CT angiography and CT myocardial perfusion) that will reduce the length of stay
as well as the consumed resources in comparison with the current approach. The additional
value of CT myocardial perfusion is to avoid false positive results by CT angiography alone.
CT myocardial perfusion will also provide incremental diagnostic value over and above CT
angiography.

STUDY DESIGN

This is a prospective open label two-arm clinical trial. Arm-A patients will receive the
standard of care diagnostic test at Baptist Hospital, which includes SPECT imaging, while
Arm-B patients will be randomized sequentially into two groups; Group-1 will receive CT
Angiography and CT myocardial perfusion with new Revolution CT scanner (General Electric
Healthcare) while the Group-2 will receive SPECT imaging test; both groups of ARM-B at West
Kendall Baptist Hospital. The study population will include a total of 250 patients
presenting at the ED with an episode of new onset chest pain. Both study arms will use the
5-Level Miami Baptist Chest Pain Protocol for triage in the ED. This chest pain protocol will
be used as previously published at Baptist Hospital and patients triaged there will serve as
a reference population (n=50), while patients (n=100) presenting at the West Kendall Baptist
Hospital will be triaged using a modified chest pain protocol which includes coronary CT
angiography and CT myocardial perfusion assessment at protocol Level 3 (and selected level 4)
instead of SPECT (Group-1) and patients (n=100) at West Kendall Baptist Hospital will receive
SPECT imaging test (Group-2). The same group of doctors will provide the interpretation for
both arms for SPECT images. All the CT scan data (including SPECT imaging, CT Angiography,
and CT myocardial perfusion) are transferred to PACS, which is a system of storing the data
electronically and can be accessed by the Radiologist. The Radiologist will be blinded to the
research patient data.

The study coordinator will collect the study data including; patient length of stay, direct
cost and CT scan data related to chest pain episode. Those patients who are discharged from
the ED will be contacted by a telephone call after 30 days for a follow-up of MACE event. In
case the patient is not available and there is no source of contact information, their
medical records will be checked or their primary care doctor will be contacted.

STUDY PROCEDURES

Patient screening will occur at the time when a patient presents at the ED of either hospital
and is assigned a categorizing level based on the 5-Level Miami Baptist Chest Pain Protocol.
Patients with an assigned "Level 3 and Level 4", who will meet all the inclusion and none of
the exclusion criteria, will be invited to participate in the study.

Informed Consent

Once the Investigator or study coordinator has determined the patient's eligibility for the
study, the background of the proposed study, the benefits and risks of the procedures will be
explained to the patient. All potential patients must agree and sign informed consent
documents prior to performing any study-specific procedures including any pre-medications.
Patients enrolled at Baptist Hospital will be treated according to the current standard of
care practice. They are being asked to consent simply according to privacy law to allow the
use of their data for further scientific evaluation. Patients enrolled at West Kendall
Baptist Hospital will consent to be treated according to a modified 5-Level Miami Baptist
Chest Pain Protocol, in which a SPECT nuclear perfusion scan is replaced by a coronary CT
angiography and a CT myocardial perfusion study for Level 3 patients, and a CT myocardial
perfusion study is added for Level 4 patients, with intermediate stenoses (40-70%), Agatston
Calcium Score >400, or non-evaluable segments in CT angiography due to calcifications, motion
artifacts, or technical reasons. Patient in ARM-B will be randomized sequentially and divided
into two groups; group-1 will receive the CT Angiography and CT myocardial perfusion while
group-2 will receive the SPECT imaging test. Patients at West Kendall Baptist Hospital will
provide consent to share their de-identified data with General Electric Healthcare for
scientific evaluation, product development, and potential marketing use. Only the West
Kendall Baptist hospital revolution study data will be shared with General Electric
Healthcare.

DATA MANAGEMENT AND STATISTICAL ANALYSIS:

All the eligible patients will be assigned a study ID and their personal information will be
strictly kept confidential. All the data will be collected and analyzed for research
purposes. The General Electric heath care will have only access to the West Kendall Arm
Revolution Computed tomography patient de-identified data. For statistical analysis, the
investigator will do the interim analysis once the enrollment and follow-up call is complete.
A biostatistician will independently analyze the data of this protocol.

SAFETY CONSIDERATIONS:

The experience of undergoing computed tomography is not uncomfortable. Computed tomography
scanning results in a measurable radiation exposure. Volume coverage of the whole heart with
axial mode results in an effective radiation dose of approximately 1 to 10 mSv, comparable to
a standard chest multi-detector computed tomography (MDCT) exam (typically 8 to 10 mSv) or
nuclear perfusion stress imaging. MDCT requires the injection of iodinated contrast agent.
This, in general, poses a risk of renal dysfunction and contrast allergy. The dose of
contrast is lower than in the majority of conventional contrast-enhanced computed tomography
studies and adequate measures will be taken to identify patients with known contrast allergy
or renal dysfunction and exclude them from participation in the study. Administration of
Metoprolol (heart beat lowering medication) might lower blood pressure and cause dizziness as
well as bronchospasm and allergic reaction. In this case, a physician will provide adequate
treatment. Patients that have known contraindications and allergy to Metoprolol are not
enrolled. The most common side effects of Regadenoson are shortness of breath, headache,
flushing, chest discomfort or chest pain, dizziness, nausea, abdominal discomfort, a metallic
taste in the mouth, and feeling hot. Most common side effects began soon after receiving
Regadenoson and went away within 15 minutes except for a headache, which is resolved in most
patients within 30 minutes

Inclusion Criteria:

1. The patient is > 35 years of age.

2. The patient had an episode of chest pain at rest or during exercise within the
previous 24 hours.

3. The patient is classified as "Level 3" in the 5-Level Miami Baptist Chest Pain
Protocol (Cury R et al. AJR, 2012; 200: 57-65) (44) or The patient is classified as
"Level 4" in the 5-Level Miami Baptist Chest Pain Protocol, and has either a 40-70%
stenosis by coronary CT angiography, an Agatston Calcium Score >400, or non-evaluable
segments in coronary CT angiography due to calcifications, motion artifacts, or other
technical reasons. (Level 4 patients who have already been scan for CTA; will not have
to repeat the CTA. Eligible Level 4 patients will only go for CT Myocardial Perfusion
scan.

4. Women of childbearing potential have a negative pregnancy urine or serum test.

5. The patient understands the study requirements and procedures and provides written
informed consent using a form that has been approved by the Institutional Review Board
(IRB) before any study specific test or procedures are performed.

6. The patient is willing to comply with the specified follow-up telephone call.

Exclusion Criteria:

1. The patient is classified as "Level 1", "Level 2", or "Level 5" in the 5-Level Miami
Baptist Chest Pain Protocol (Cury R et al. AJR, 2012; 200: 57-65). This includes
patients with STEMI (Level-1), NSTEMI or Unstable Angina (Level-2) and non-cardiac
chest pain patients (Level-5)

2. Known allergy to iodinated contrast agent or creatinine >1.5mmol/L.

3. Atrial Fibrillation, Flutter or irregular heart rhythm.

4. Known history of severe asthma.

5. Body Mass Index (BMI) >45.

6. Patients in unstable conditions.