Dynamic Computed Tomography Myocardial Perfusion Imaging for Detection of Coronary Artery Disease

This will be a prospective study comparing the low-dose dynamic vs. static CTP combined with the CTA for detecting hemodynamically significant coronary artery stenosis. The aim of the study is to assess the feasibility, safety and accuracy of low-dose dynamic CTP following CTA.

The study will enroll patients who have documented coronary artery disease and an indication for coronary angiography or CT angiography. Referred patients will be assessed for eligibility through phone calls followed by in-person interviews. Patents will be provided with the informed consent forms for CTA-CTP and iodine contrast if it is determined that participants are eligible for the study. Patients have the right to refuse to participate in the study and in that case participants will receive the regular care, per clinical guidelines. Baseline information will be collected from the patients after participants consent to participate in the study. Baseline data collection will happen at the same day that the patients will undergo CTA-CTP. The CTA-CTP acquisition takes less than 60 minutes after the patient is on the CT scanner table. Patient preparation time before patient is brought on the CT scanner depends on patients' heart rate and the time that takes to reduce patient's heart rate to a level that is appropriate for CTA-CTP acquisition. The blood sample will be obtained from the patients at the same day as CTA-CTP acquisition. Patients will be discharged to home at the same day participants undergo CTA-CTP.

1. Study duration and number of study visits required of research participants. There will be only one visit required for the purposes of the study, during which the CTA-CTP acquisition will be completed, baseline information will be collected and the blood samples will be drawn. The study participants will be contacted through phone 3-days after CTA-CTP acquisition for follow-up.

CT Imaging protocol

Patients will have two 18-20 gauge intravenous lines placed, one preferably in an antecubital vein for contrast administration. The patient will be hydrated with normal saline intravenously (250 - 500 ml) prior to 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 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. A physician will be present at all times during adenosine infusion and CT imaging. Patients may receive an oral and/or intravenous dose of metoprolol up to one hour prior to the CT. If the heart rate is >60 beats per minute, 75 mg (max 80 mg) of metoprolol will be given orally. If Heart rate remains >60 beats per minute at the scan acquisition then, intravenous beta blocker (metoprolol, propranolol or landiolol) 2.5 - 5.0 mg every 5 minutes will be administered to achieve a heart rate between <60 beats per minute as blood pressure tolerates under the supervision of a physician. Scout images for determining scanning range will be obtained in the anterior-posterior and lateral views. Patients with systolic blood pressure ≥110 will receive sublingual fast acting short lasting nitrates (e.g. nitroglycerin, isosorbide dinitrate). Patients will then be asked to hold their 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. CT angiogram will be performed to evaluate the coronaries and myocardial perfusion at rest. Blood pressure will be checked and intravenous adenosine infusion (0.14 mg/kg/min) will begin with continuous heart rate and rhythm monitoring. After 5 minutes of adenosine infusion, contrast-enhanced CT perfusion imaging will be performed during a 4-5 ml/sec intravenous iodinated contrast (ISOVUE®-370) infusion. Total contrast dose for the entire protocol will not exceed 140 ml and will be based on patient's body size. Patients will be asked to hold their breath during scanning. Immediately following completion of the scan, the adenosine infusion will be discontinued. A twelve lead ECG and blood pressure measurement will be repeated after discontinuation of adenosine and reviewed by a physician. Intravenous hydration will be continued during recovery with normal saline for a total volume for the entire post scan of 250 to 500 ml if deemed appropriate by the supervising physician.

320-Detector CT Protocol for Combined Coronary Angiography and Perfusion Imaging

1. Coronary calcium scan will be performed using the following protocol:

• No contrast.
• CT Imaging: tube voltage = 120kV, tube current = 140 Milliampere (mA), gantry rotation speed = 0.35 seconds, slice thickness = 0.5 mm, rows = 256-320, range = 128-160 mm. X-ray tube will be on for a total of 0.35 seconds. Estimated radiation dose = 1.5 Millisievert (mSv).

1. Rest coronary arterial imaging Rest perfusion and coronary arterial imaging will be performed during a 4-5 ml/sec intravenous iodinated contrast (ISOVUE®-370) infusion. The rest CTA-dynamic CTP images will be started using a test bolus acquisition and accurate quantification of optimum timing for dynamic CTP and boost CTA acquisition and will continue for 20-30 sec using a ECG triggering method to allow acquiring the images only within 70-80% of the R-R interval, but not continuously. The parameters for the dynamic CTP image acquisition are the followings: For the heart rate of <60 bpm the tube voltage will be 80 kV and the tube current will be 100mA. Other parameters are: gantry rotation=0.275, range=120mm. The CTA and static CTP imaging will be performed as a boost scan during the dynamic CTP with the same tube voltage (80kV) but the tube current of 600mA within 70-80% of R-R interval. The boost timing will be quantified from test bolus acquisition. The average radiation dose for rest CTA and rest dynamic and static CTP acquisition is 3.69mSv.
2. Stress Myocardial Perfusion imaging 20 minutes after rest image acquisition Blood pressure will be checked and intravenous adenosine infusion will begin with continuous heart rate and rhythm monitoring. After 5 minutes of adenosine infusion, contrast-enhanced CT perfusion imaging will be performed during a 4-5 ml/sec intravenous iodinated contrast (ISOVUE®-370) infusion. The stress dynamic CTP images will be started using a test bolus acquisition and accurate quantification of optimum timing for dynamic CTP and boost CTA acquisition and will continue for 20-30 sec using a ECG triggering method to allow acquiring the images only within 70-80% of the R-R interval, but not continuously. The parameters for the stress dynamic CTP image acquisition are the followings: For the heart rate of <80 bpm the tube voltage will be 80 kV and the tube current will be 100mA. Other parameters are: gantry rotation=0.275, range=120mm. The stress static CTP imaging will be performed as a boost scan during the stress dynamic CTP with the same tube voltage (80kV) but the tube current of 600mA within 70-80% of R-R interval. The boost timing will be quantified from test bolus acquisition. The average radiation dose for stress dynamic and static CTP acquisition is 5.17mSv.

The estimated average radiation dose for the entire cardiac computed protocol is 10.55 mSv and shall not exceed 15mSv. Beta-blockers will be used to control the heart rate and thus maintain the radiation dose as low as reasonably achievable. The total contrast dose will not exceed 140 ml. Depending on patient size, 50-70 ml of iodinated contrast will be used for each of rest and stress scans.

In the event that the CT raw data are not readable at the Johns Hopkins University, a copy of the raw data (anonymized without patient identifiers) will be transferred to Toshiba Medical Systems for engineering support of image reconstruction in these isolated cases. Toshiba Medical Systems will perform the image reconstruction and return the raw data and the reconstructed image data to the Johns Hopkins University for image analysis.

Within 3 weeks of the CT, the CT will be reviewed for non-cardiac findings by a locally qualified, institutionally approved cardiologist and reported to the patient's clinical physician and patient in a timely fashion preferably prior to or during the 30-day follow-up.

1. Blinding, including justification for blinding or not blinding the trial, if applicable.

Dynamic and static CTP images will be analyzed separately and when analyzing the CTP images with each method, the readers will be blinded to the results the other method. However the readers will have access to the results for CTA interpretation while reading the CTP images with either of static or dynamic methods.

1. Justification of why participants will not receive routine care or will have current therapy stopped.

The study will be only enrolling patients with an indication for CTA or invasive coronary angiography and will undergo these tests. So routine care will be delivered to the participants.

1. Study Statistics
2. Primary outcome variable. The primary outcome measures will be feasibility, safety and accuracy of dynamic CTP-CTA compared to static CTP-CTA to detect hemodynamically significant coronary artery stenosis. The hemodynamically significant coronary artery stenosis will be defined as having at least one vessel with a ≥50% stenosis associated with perfusion defect in static CTP images.

At the index visit, failure to complete the CTP protocol will constitute an incomplete study and such patients will be excluded from the per protocol analysis. All patients completing the CTP protocol and providing informed consent will be included in per-protocol analyses. All data from all consented patients who do not complete the CTP protocol will be included in the intent-to-diagnose analysis.

Descriptive statistics will be given for all variables including indications for the test, demographics, patient history, CTA test information, dynamic and static CTP information. Categorical variables will be summarized as counts and percentages. All continuous variables will be summarized as means+/- the standard deviation followed by the median, minimum and maximum and 25th, 75th percentiles where needed.

The frequency of the primary safety outcomes [death, myocardial infarction, unstable angina, ventricular tachycardia, asystole, severe bradycardia, allergic skin reactions, allergic respiratory reactions, hypotension, anaphylaxis and contrast induced nephropathy] will all be summarized; 95% binomial confidence intervals for the proportions of these outcomes will be calculated. The additional safety outcomes involving CTP complications will be summarized with frequencies and 95% confidence intervals for proportions. Radiation dose and efficiency measures (duration(s) involving the CTP procedure) will be summarized overall with median and 25th and 75th percentiles. Also minima and maxima will be provided. The investigators may explore possible associations between patient characteristics [demographics (gender, age), prior histories or indications] and the binary safety outcomes using contingency table methods, t tests or Wilcoxon Rank Sum, as appropriate. Associations between radiation dose and patient characteristics may be explored with nonparametric methods. The investigators may also explore possible relationships between the CTA stenosis categories (0%, 1-49%, 50-100%) and the dynamic and static CTP results. The occurrence of clinical events recorded at 30-day chart review will be related to the category of CTP final results (Normal, Probably Normal, Equivocal, Probably Abnormal and Abnormal) using methods for contingency tables which incorporate the natural ordering of CTP categories.

The frequency of the studies with the adequate image quality for interpretation of dynamic CTP images will be reported as a measure is feasibility. This feasibility index will be also reported at the myocardial segment level and the frequency of Left Ventricular (LV) segments with adequate dynamic CTP image quality will be reported.

The inter- and intra-reader reproducibility of dynamic CTP interpretation will be assessed using kappa statistics, intra-class correlation coefficients and Bland-Altman plot, as appropriate.

The accuracy of the dynamic CTP for detection of hemodynamically significant coronary artery stenosis will be based on the area under the receiver operating characteristic (ROC) curve (AUC) with the static CTP results as the comparator. The correlation of the dynamic vs. static CTP will be also assessed in the categorical (Chi-squared test) and continuous (Spearman's correlation coefficient) scale.