Ultra-high-resolution CT vs. Conventional Angiography for Detecting Coronary Heart Disease
Ultra-high-resolution CT vs. Conventional Angiography for Detecting Coronary Heart Disease
Cardiac catheterization with invasive coronary angiography is the gold standard for
 determining the presence or absence of significant coronary heart disease (CHD). However,
 cardiac catheterization is costly and, as an invasive procedure, it is associated with some
 risk of adverse events, rarely even stroke, myocardial infarction, or death. Recent advances
 in multi-detector computed tomography angiography (CTA) have allowed rapid, noninvasive
 coronary artery imaging in patients with suspected CHD. CTA generally yields high accuracy
 for identifying patients with CHD when compared to cardiac catheterization. However,
 diagnostic accuracy is reduced in the setting of severe coronary artery calcification and
 coronary stents due to its inferior spatial resolution compared to cardiac catheterization.
 Because high-risk patients often have severe coronary calcification or stents, the
 application of CTA has been particularly limited in this important patient group. Recently,
 an ultrahigh-resolution CT scanner was released which has shown promise to overcome the
 limitation of conventional CTA in the setting of severe coronary artery calcification or
 stents. This ultrahigh-resolution "precision" CT scanner (UHR-CT) contains detector rows with
 half the width than currently available systems (0.25 mm vs. 0.5 mm) resulting in
 approximately twice the spatial resolution.

 The purpose of this investigation is to test the hypothesis that high-resolution CTA is not
 inferior to the current standard of cardiac catheterization for identifying significant CHD
 in patients with high-risk characteristics, including severe coronary artery calcification
 and coronary stents.

 The investigators propose to enroll 43 patients over 24 months in this pilot investigation.
 Patients referred for cardiac catheterization with known CHD and suspected obstructive
 coronary artery stenosis will be included. All patients will undergo both cardiac
 catheterization and UHR-CT for determining significant CHD as defined by coronary functional
 assessment. The primary end point will be the diagnostic accuracy by area-under-curve (AUC)
 method for identifying patients with hemodynamically significant CHD.
Primary Objective The primary objective of this study is to generate preliminary data in
 support of the hypothesis that noninvasive UHR-CT is not inferior to invasive coronary
 angiography by cardiac catheterization for identifying patients with hemodynamically
 significant CHD.

 Secondary Objectives Secondary objectives include testing the diagnostic accuracy of UHR-CT
 vs. cardiac catheterization on a vessel and segment based analysis, comparison of UHR-CT
 Fractional Flow Reserve (FFR) to conventional angiography, and comparison of adverse events
 and radiation doses between the CT and conventional angiography groups.

 Patient-Based Hypotheses

 1. Diagnostic accuracy of UHR-CT using visual assessment of coronary artery disease is
 non-inferior to invasive, conventional coronary angiography for identifying patients
 with hemodynamically significant CHD defined by an FFR or QFR-value of <0.8 in at least
 one vessel of 2.0 mm or larger in diameter.

 2. Diagnostic accuracy of UHR-CT using quantitative assessment of coronary artery disease
 is non-inferior to invasive, conventional coronary angiography for identifying patients
 with hemodynamically significant CHD defined by an FFR-value of <0.8 in at least one
 vessel of 2.0 mm or larger in diameter.

 3. Diagnostic accuracy of UHR-CT using CT-FFR is non-inferior to invasive, conventional
 coronary angiography for identifying patients with hemodynamically significant CHD
 defined by an FFR-value of <0.8 in at least one vessel of 2.0 mm or larger in diameter.

 4. UHR-CT coronary angiography is associated with lower radiation dose than conventional,
 invasive coronary angiography.

 5. UHR-CT coronary angiography is associated with lower adverse effects than conventional,
 invasive coronary angiography.

 Vessel Based Hypotheses

 1. Diagnostic accuracy of UHR-CT using visual assessment of coronary artery disease is
 non-inferior to invasive, conventional coronary angiography for identifying vessels with
 hemodynamically significant CHD defined by an FFR or QFR-value of <0.8 in a vessel of
 2.0 mm or larger in diameter.

 2. Diagnostic accuracy of UHR-CT using quantitative assessment of coronary artery disease
 is non-inferior to invasive, conventional coronary angiography for identifying vessels
 with hemodynamically significant CHD defined by an FFR-value of <0.8 in a vessel of 2.0
 mm or larger in diameter.

 3. Diagnostic accuracy of UHR-CT using CT-FFR is non-inferior to invasive, conventional
 coronary angiography for identifying vessels with hemodynamically significant CHD
 defined by an FFR-value of <0.8 in a vessel of 2.0 mm or larger in diameter.

 Segment-Based Hypotheses

 4. Diagnostic accuracy of UHR-CT using visual assessment of coronary artery disease is
 non-inferior to invasive, conventional coronary angiography for identifying arterial
 segments with hemodynamically significant CHD defined by an FFR-value of <0.8 in a
 vessel of 2.0 mm or larger in diameter.

 5. Diagnostic accuracy of UHR-CT using quantitative assessment of coronary artery disease
 is non-inferior to invasive, conventional coronary angiography for identifying arterial
 segments with hemodynamically significant CHD defined by an FFR-value of <0.8 in a
 vessel of 2.0 mm or larger in diameter.

 3. Background Cardiac catheterization with invasive coronary angiography has remained the
 gold standard for determining the presence or absence of significant coronary luminal
 stenosis despite its limited accuracy compared to the standard of intravascular ultrasound.
 Because of the inherent risks involved with this invasive procedure (e.g., stroke, myocardial
 infarction, death or need for emergency surgical intervention) with a major complication rate
 of 1-2%), and considerable costs, non-invasive assessment of coronary artery disease would be
 preferred. Advances in multi-detector computed tomography angiography (CTA) have made the
 non-invasive imaging of the coronary arterial lumen and wall feasible. Numerous studies have
 since demonstrated good accuracy of CTA to identify patients with obstructive coronary artery
 disease. However, studies also demonstrated that CTA's diagnostic accuracy is only modest in
 patients with severe coronary artery calcification or stents, representing a major limitation
 of the technology. This limitation is due to fair spatial resolution and associated image
 artifacts in the setting of an attenuation-based image reconstruction algorithm. In this
 situation, high density structures, such as calcium or metal, will disproportionally dominate
 information derived from an affected image voxel leading overrepresentation of these
 structures on image display (partial volume effect).

 Recently, an ultrahigh-resolution CT scanner has been released which has shown promise to
 overcome the limitation of conventional CTA in the setting of severe coronary artery
 calcification or stents. This ultrahigh-resolution "precision" CT scanner (UHR-CT) contains
 detector rows with half the width than currently available systems (0.25 mm vs. 0.5 mm)
 resulting in approximately twice the spatial resolution. It is likely that this improvement
 will lead to improved diagnostic accuracy in high-risk patients. To conclusively test this
 hypothesis, a larger, multi-center study is required. The purpose of this investigation is to
 test the feasibility of such study and to generate initial data on the hypothesis that
 high-resolution CTA is not inferior to the current standard of cardiac catheterization for
 identifying significant CHD in patients with high-risk characteristics.

 4. Study Procedures

 a) Study design The CORE (CORonaryEvaluation)-PRECISION Pilot study is a prospective single
 center study of comparing the diagnostic accuracy of UHR-CT to conventional, invasive
 coronary angiography by cardiac catheterization for the presence of hemodynamically
 significant CHD in 43 patients with CHD. For each participant, the screening evaluation
 periods will last less than 60 days and will be followed by the imaging period (less than 60
 days). All patients will be followed by additional 30 days after cardiac catheterization for
 occurrence of adverse events.

 Screening-Evaluation Period: The screening period will begin when a patient is scheduled for
 a clinically indicated coronary angiogram. The protocol inclusion and exclusion criteria will
 be reviewed for each potential participant. If the patient appears to be eligible for the
 study based on the initial evaluation, informed consent will be obtained. Baseline
 information and medical history will be collected. Blood will be obtained at the time of CTA
 (during intravenous cannula [IV] placement) for laboratory testing of cholesterol profile and
 serum biomarkers. No genetic testing will be performed.

 The clinically indicated coronary angiogram will not be delayed to complete the research
 protocol. If the CTA scan cannot be scheduled prior to the clinically indicated coronary
 angiogram the patient will not be enrolled in the trial. Consented patients will continue to
 be evaluated for participation in the trial through the imaging period.

 Imaging Period The imaging period will consist of two tests: 1) ultra-high resolution CT
 (UHR-CT) angiography; 2) conventional coronary angiography (CTA). All enrolled patients
 referred for a clinically indicated catheterization will first a UHR-CT angiogram.

 UHR-CT Imaging Patients will have one 18-20 gauge intravenous lines placed, preferably in an
 antecubital vein for contrast administration. The patient will be hydrated with normal saline
 intravenously (250 - 500 ml) prior to UHR-CT scanning. The patient will lie supine on the
 scanner table and be attached to a 12 lead electrocardiographic monitor and an automated
 blood pressure monitor. Baseline electrocardiogram (ECG), heart rate, and blood pressure will
 be recorded and reviewed by one of the study investigators. Due to resultant artifacts from
 precordial leads, the 12 ECG leads and electrodes will be removed and rhythm monitoring will
 continue using the 3-lead system attached to the scanners monitoring system during scanning.
 Patients may receive oral metoprolol and/or oral ivabradine 1-2 hours prior to the CT
 according to a hospital approved heart rate control algorithm. Specifically, if the heart
 rate (HR) is >70 beats per minute, 50 mg of oral metoprolol will be given along with 15 mg of
 oral ivabradine. If the heart rate is >65 but lower than 70 beats per minute, 25 mg of oral
 metoprolol will be given along with 15 mg of oral ivabradine. If the heart rate is >60 beats
 per minute but lower than 65 beats, only 15 mg of ivabradine is given. If HR remains >60
 beats per minute after 60 minutes post initial dosing of metoprolol and ivabradine, a second
 doses of 25-50 mg oral metoprolol is given. Scout images for determining scanning range will
 be obtained in the anterior-posterior and lateral views. Patients with systolic blood
 pressure ≥110 will receive 0.8 mg sublingual nitroglycerin for vasodilation. The adequate
 calcium score scan protocol will be confirmed on the scanner for each participant prior to
 the initiation of the calcium score scan. Patients will then be asked to hold patients'
 breath (approximately 10-15 seconds) and non-contrast CT imaging will be performed starting
 just cranial to the coronary ostia and extending just caudal to the apex of the heart in
 order to obtain a coronary calcium score. To limit radiation exposure, a coronary calcium
 score will only be generated for patients who have not previously been stented as the
 presence of stents affects the accuracy of the calcium score. CT angiogram will then be
 performed to evaluate the coronaries using iodine contrast.

 UHR-CT Protocol for Coronary Angiography

 1. If no previous stents, coronary calcium scan will be performed using the following
 protocol:

 -  No contrast.

 -  CT Imaging: tube voltage = 120 kilovolt (kV), tube current = 140 milliAmpere (mA),
 gantry rotation speed = 0.275 seconds, slice thickness = 0.25 mm, rows = 100, range
 = 40 mm. Estimated radiation dose = 1.0-2.5 milli-Sievert (mSv).

 2. Coronary arterial imaging Coronary arterial imaging will be performed during a 4-6
 ml/sec intravenous iodinated contrast iohexol (Omnipaque-350) infusion for a total
 volume of 60-100 ml. The automated bolus tracking feature will be used to judge contrast
 bolus arrival and optimize image quality. Bolus tracking will result in approximately
 0.7-1.2 mSv radiation dose to the patient (weight dependent).

 Images will be prospectively triggered using ECG gating which reduces radiation exposure to
 the patient compared to retrospective gating. The estimated range of radiation dose for CT
 coronary angiography will be 3.2-8.0 mSv depending on patient size and weight.

 Total estimated radiation dose, including calcium scoring, bolus tracking, and CT coronary
 angiography, will therefore range between 4.9-11.7 mSv. For comparison, a standard nuclear
 stress test typically results in a radiation dose of 10-12 mSv to the patient. Diagnostic
 cardiac catheterization for conventional coronary angiography typically averages 12 mSv
 radiation dose.

 CT raw data and reconstructed data will be saved by the site for at least 2 years after
 completion of the study. Within 3 weeks of the CTA, the CTA will be reviewed for non-cardiac
 findings by a locally qualified, institutionally approved radiologist, and reported. The
 investigator will report these findings to the patient's clinical physician and patient in a
 timely fashion preferably prior to or during the 30-day follow-up.

 A pre-catheterization serum creatinine should be obtained post CTA (per local standard, or
 preferably > 3 days post CTA).

 Conventional Coronary Angiography Patients will undergo patients' clinically indicated
 cardiac catheterization/coronary angiography, within 60 days of CT imaging with a recommended
 goal of completing all imaging within 30 days. A time window of ≥ 48 hours is recommended
 between CT imaging and conventional coronary angiography to minimize cumulative risk of
 contrast exposure from these two tests. Coronary angiography guidelines to obtain optimum
 angles and images for comparison will be enforced. Isocenter calibration will be performed
 for all studies to enable quantitative flow reserve (QFR) assessment. Intracoronary
 nitroglycerine will be administered (150-200 mcg) prior to first image of the left coronary
 artery system and right coronary artery. This is to standardize the vasomotor state of the
 coronary artery and eliminate any potential for catheter-induced changes (i.e., catheter
 induced spasm).

 Fractional-flow-reserve (FFR) assessment will be performed as clinically indicated but not
 solely for research purposes. Coronary angiographic images will be saved in the universal
 DICOM format and forwarded to the Angiographic Core Laboratory for Quantitative Coronary
 Angiographic Analysis. Quantitative coronary analysis (QCA) will be performed using standard,
 validated analysis software from Pie Medical Systems. QFR will be performed using a dedicated
 software (QFR, Medis Medical Imaging Systems).

 A post-catheterization serum creatinine should be obtained per local standard, or preferably
 within 48-72h post invasive coronary angiogram. Primary Objective The primary objective of
 this study is to generate preliminary data in support of the hypothesis that noninvasive
 UHR-CT is not inferior to invasive coronary angiography by cardiac catheterization for
 identifying patients with hemodynamically significant CHD.

 Secondary Objectives Secondary objectives include testing the diagnostic accuracy of UHR-CT
 vs. cardiac catheterization on a vessel and segment based analysis, comparison of UHR-CT
 Fractional Flow Reserve (FFR) to conventional angiography, and comparison of adverse events
 and radiation doses between the CT and conventional angiography groups.
Inclusion Criteria:

 -  Patients aged 45-85 years with history of CHD will be asked to participate. History of
 CHD is defined as prior documentation of a coronary artery stenosis of 50% or greater
 by coronary angiography or by prior documentation of coronary artery revascularization
 by percutaneous coronary intervention (PCI). Women of child bearing potential must
 demonstrate a negative pregnancy test within 24 hours of the study CTA.

 -  Suspected obstructive coronary artery stenosis based on clinical history and/or
 noninvasive testing, prompting a clinical referral for invasive coronary angiography;
 and/or planned PCI within the next 60 days.

 -  Ability to understand and willingness to sign the Informed Consent Form.

 Exclusion Criteria:

 -  Known allergy to iodinated contrast media

 -  History of multiple myeloma or previous organ transplantation

 -  Elevated serum creatinine (> 1.5mg/dl) or calculated creatinine clearance of < 60
 ml/min (using the Cockcroft-Gault formula

 -  Atrial fibrillation or uncontrolled tachyarrhythmia, or advanced atrioventricular
 block (second or third degree heart block)

 -  Evidence of severe symptomatic heart failure (NYHA Class III or IV);

 -  Known or suspected moderate or severe aortic stenosis

 -  Previous coronary artery bypass or other cardiac surgery

 -  Suspected acute coronary syndrome

 -  Presence of any other history or condition that the investigator feels would be
 problematic