Ultra-high-resolution CT vs. Conventional Angiography for Detecting Coronary Heart Disease

1. Objectives: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. UHR-CT coronary angiography is associated with lower radiation dose than conventional, invasive coronary angiography.
4. 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 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. Lesion-Based Hypotheses
3. Diagnostic accuracy of UHR-CT using visual assessment of coronary artery disease is non-inferior to invasive, conventional coronary angiography for identifying lesions with hemodynamically significant CHD defined by an QFR-value of <0.8 in a vessel of 2.0 mm or larger in diameter.
4. Diagnostic accuracy of UHR-CT using quantitative assessment of coronary artery disease is non-inferior to invasive, conventional coronary angiography for identifying lesions with hemodynamically significant CHD defined by an QFR-value of <0.8 in a vessel of 2.0 mm or larger in diameter.
5. 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.

1. Study Procedures
2. Study design: The CORE-PRECISION MULTI-CENTER study is a prospective diagnostic accuracy study at three international sites comparing the diagnostic accuracy of UHR-CT to conventional, invasive coronary angiography by cardiac catheterization for the presence of hemodynamically significant CHD in 150 patients with high pretest probability of obstructive CHD. The enrollment at all centers is expected to commence in the summer of 2022: Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center, Baltimore, USA, Iwate University Medical Center, Iwate, Japan, and Einstein Medical Center, Sao Paulo, Brazil. Sites will obtain approval from the local Institutional Review Board and all patients will sign informed consent prior to participation Each study site is expected to enroll 50 participants. Enrollment has been ongoing since November of 2019 at Johns Hopkins University as part of a pilot study using the same protocol with minor variations. For each participant, it is anticipated that the Screening Evaluation Periods will last less than 2 months 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. Patients without history of Coronary Artery Disease (CAD) may enter an extended screening period that involves the first component of the CT imaging examination, namely the coronary calcium scan. If this scan shows a calcium score <400, these patients will be considered late screen failures, will not proceed to contrast-enhanced coronary CT angiography, and will be excluded from further participation in the trial. Patients with a calcium score of 400 or greater will proceed to coronary CT angiography and study participation.

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. All enrolled patients referred for a clinically indicated catheterization will first receive a UHR-CT angiogram to avoid conflict with coronary artery revascularization

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 ≥100 will receive 0.4-1.2 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 = 150 milliAmpere (mA), gantry rotation speed = 0.230 seconds for half rotation, slice thickness = 0.25 mm, rows = 100, range = 144 mm. Estimated radiation dose = 0.5--2.0 milli-Sievert (mSv).

1. Coronary arterial imaging will be performed during a 4-6 ml/sec intravenous iodinated contrast infusion for a total volume of 60-120 ml. The automated bolus tracking feature will be used to judge contrast bolus arrival and optimize image quality.

Images will be prospectively triggered using ECG gating which reduces radiation exposure to the patient compared to retrospective gating. Tube voltage and current will be adjusted according to image noise characteristics during scout imaging. A tube setting of 120 kV with 580 mA will be required for most patients in the setting of severe calcification and/or stenting. Target exposure will be 70-80% of the R-R cycle for heart rate ≤60 bpm. Heart rate of 61-70 will require a widened exposure window of 65-85% of the R-R cycle. Gantry rotation will be 350 ms with a 160 x 0.25 mm collimation in super high resolution mode, requiring approximately 6.5 second scan time. The estimated range of radiation dose for CT coronary angiography will be 4.3.0-10.7 mSv depending on patient size and weight.

Total estimated radiation dose, including calcium scoring, bolus tracking, and CT coronary angiography, will therefore range between 4.8-12.7 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.

A copy of the anonymized raw data (without any patient identifiers) will be forwarded to the CT Core Laboratory for analysis within 1 week of the scan. CT raw data and reconstructed data will be saved by the site for at least 5 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 > 2 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 ≥ 24-48 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 may 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 Medis Medical Systems (Medis QCA). 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.