In the multicenter registry, we pooled data on patients from six centers in Asia, Europe, and North America who had undergone CCTA and dynamic myocardial perfusion CT between November 2009 and July 2011 as part of single-center studies. Patients were eligible if they had suspected or known CAD. Patients were not considered for study inclusion if they had contraindications to CT or to administration of iodinated contrast medium or adenosine. The respective research study protocols had been approved by the institutional review boards of all participating institutions, and written informed consent had been obtained from all research subjects before enrollment. The dynamic myocardial perfusion CT examinations were investigational. The results of these examinations were not reported or disclosed to clinicians and were not used to guide management decisions.

At myocardial perfusion CT, the following demographic parameters and baseline clinical risk factors were collected for all patients: age; sex; history of diabetes, hypertension, or dyslipidemia; history of smoking (current or former smoker); personal history of CAD (previous myocardial infarction or previous angiographically documented clinically significant CAD); and family history of CAD. The total number (range, 0–6) of these cardiac risk factors was determined.

All image acquisitions were performed with a second-generation dual-source CT system (Somatom Definition Flash, Siemens Healthcare). Initially, CCTA was performed at rest after IV administration of 50–80 mL of iodinated contrast agent (concentration, 300–370 mg I/mL). Depending on the patient's heart rate and rhythm, CCTA was performed with retrospective ECG gating (patients with arrhythmia), prospectively ECG-triggered sequential acquisition (patients in sinus rhythm with a heart rate > 60 beats/min), or prospectively ECG-triggered high-pitch spiral acquisition (patients in sinus rhythm with a heart rate ≤ 60 beats/min).

After 3 minutes of continuous adenosine administration at an infusion rate of 140 μg/kg/min, myocardial perfusion CT acquisition was initiated. The scan delay was determined with a test bolus injection and set 4–6 seconds before arrival of the contrast agent in the aorta. Data acquisition was performed for 30 seconds with both x-ray tubes set at 100 kV, gantry rotation time of 0.28 seconds, and tube current of 300 mAs per rotation. Perfusion imaging was performed with an ECG-triggered shuttle mode in which the table shifted between two z-positions of the heart. Image acquisition was performed in systole 250 ms after the R wave. With a defined detector width of 38 mm, and 10% overlap between the two imaging positions, the coverage of the acquisition was 73 mm. A total of 14–15 image volumes during myocardial passage of the contrast bolus were acquired for each patient. Myocardial perfusion CT studies were contrast enhanced with 40–50 mL of iodinated contrast agent (concentration, 300–370 mg I/mL) administered at a flow rate of 4–7.5 mL/s to ensure an iodine delivery rate of 1.5–2.25 g I/s.

Analysis of all CCTA and myocardial perfusion CT data was performed in a central core laboratory at one site. All CCTA data were reconstructed with a section thickness of 0.75 mm and 0–5 mm increments with a vascular reconstruction kernel (B26F). Two experienced readers (3 and 6 years of experience in cardiac CT interpretation) independently evaluated all CCTA studies. For CAD evaluation, vessel-based analysis was performed to evaluate the presence of stenosis in the left anterior descending, left circumflex, and right coronary arteries. The left main coronary artery was included with the left anterior descending. Coronary artery dominance (right, left, or balanced) was recorded. The degree of stenosis was assessed with multiplanar reconstructions and curved multiplanar reconstructions along the vessel centerline (Circulation, Siemens Healthcare). Vessels were visually assessed as to whether they harbored stenosis with 50% or greater luminal narrowing. If the lumen of a given vessel was not evaluable because of the presence of heavy calcifications or motion artifacts, it was rated nondiagnostic. For the data analysis, these vessels were considered to have 50% or greater stenosis according to an intention-to-diagnose approach to avoid the risk of overlooking any stenoses possibly present in nondiagnostic vessels. Myocardial regions were then matched to the supplying vessels. Discordant findings were resolved in a final consensus reading with a third observer (more than 15 years of experience in cardiac CT). The results of this consensus interpretation were used for statistical analysis.

Qualitative interpretation of myocardial perfusion CT studies was performed independently by the two readers. Each vessel territory was assessed for the presence of perfusion defects. For this purpose, reconstructed perfusion datasets were viewed with dedicated software (VPCT body application, Syngo MMWP workstation, Siemens Healthcare), which analyzes and displays parameters of the myocardial blood supply, including myocardial blood flow and myocardial blood volume, as parametric maps. Visual analysis of myocardial perfusion CT data were performed in side-by-side correlation with CCTA studies to directly match perfusion defects to the supplying vessels. To ensure correct identification of vascular territories, angiographic visualization of vessel dominance was used to decide which vessel supplied the inferior and inferoseptal regions. A vessel territory was considered to harbor a perfusion defect if an area of decreased myocardial blood flow, volume, or both was present that was consistent with an ischemic cause and not suggestive of an artifact (whether or not ≥ 50% stenosis was detected in the supplying vessel at CCTA). Myocardial perfusion CT studies were viewed in axial, coronal, and sagittal orientation for reliable differentiation of artifacts from true perfusion defects. Any discrepancies between the two readers were resolved by consulting the third experienced reader. A myocardial perfusion CT stress test result was classified as positive if one or more territories had a perfusion deficit.

Prospective follow-up was conducted at each site by chart review and telephone interviews with the patient or a close relative 6, 12, and 18 months after imaging. Outcome data were collected from a standardized questionnaire. Reported clinical events were confirmed by contact with the patient's primary care physician or the admitting hospital. The occurrence of MACE was recorded at each time point. If an event was registered during follow-up but the exact time of the event could not be determined, it was assumed that the event occurred at the end of the 6-month time interval since the last follow-up examination because this would result in the most conservative risk estimates. MACE were defined as cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, or revascularization (percutaneous coronary intervention or coronary artery bypass grafting).

Continuous data (age) were tested for normal distribution by Kolmogorov-Smirnov test and found to be not normally distributed. Thus, age was presented as median and interquartile range (25th–75th percentile) and compared by nonparametric Mann-Whitney test. Categoric data were displayed as absolute frequencies and proportions. The chi-square test was used to compare the frequency distribution of binary data between groups. The chi-square test for trend was used to compare the distribution of the number of affected vessels or territories. Patients were divided into groups according to the number of vessels with 50% or greater stenosis and according to the number of vascular territories with perfusion defects.

Cumulative event rates stratified by CCTA and myocardial perfusion CT features were analyzed with Kaplan-Meier survival curves fitted for MACE with patient data censored after the first event. The log-rank test was used to test for significant differences in cumulative event rates between groups. The univariate Cox proportional hazards regression model was used to analyze the predictive value of findings at CCTA and myocardial perfusion CT for MACE during follow-up. Adjusted Cox proportional hazards models were used to evaluate whether the predictive value of CCTA and myocardial perfusion CT findings was independent of age, sex, and clinical risk factors and whether findings at myocardial perfusion CT had predictive value independent of findings at CCTA. The first model was adjusted for sex and number of clinical risk factors (hypertension, hyperlipidemia, diabetes, smoking history, history of CAD, family history of CAD) with block entry of all variables. The second model additionally incorporated the number of vessels with 50% or greater stenosis at CCTA. All statistical analyses were performed with MedCalc Statistical Software (version 12.7.2, MedCalc Software). Two-sided p < 0.05 was considered to indicate statistical significance.

Data on a total of 242 patients from six centers in Asia, Europe, and North America were pooled in a registry (Fig. 1). Eighty-two patients were excluded from the analysis because of missing follow-up data, missing or incomplete myocardial perfusion CT data, presence of severe artifacts in the perfusion dataset, or substantial portion of the myocardium not covered by the myocardial perfusion CT acquisition. Sixteen of the other 160 patients had a history of previous coronary revascularization (percutaneous coronary intervention [n = 14] or coronary artery bypass grafting [n = 2]) and were excluded from the final analysis. The final patient population consisted of 144 patients from five centers (111 men [77.1%]; 33 women [22.9%]; median age, 61 years; interquartile range, 54–65 years) at intermediate to high cardiovascular risk who underwent CCTA and myocardial perfusion CT for known or suspected CAD. Age, sex, and clinical risk factors did not have statistically significant predictive value for MACE (Table 1), although a trend toward higher risk among men was observed (hazard ratio [HR], 2.03; 95% CI, 0.85–4.82; p = 0.1109).

CCTA showed that 112 of 432 evaluated vessels (25.9%) had stenosis with 50% or greater luminal narrowing. At least one clinically significant stenosis was found in 62 of 144 patients (43.1%) (Table 2). Four patients with left-dominant coronary circulation did not have a left ventricular myocardial territory supplied by the right coronary artery. Therefore, myocardial perfusion was analyzed in 428 vascular territories in 144 patients. Overall, 83 vessel territories (19.4%) in 51 patients (35.4%) had a perfusion defect at visual analysis of myocardial perfusion CT data (Table 2). Imaging findings of representative patients are shown in Figures 2–4.

The median follow-up period was 12 months (range, 6–18 months). Forty patients (27.7%) experienced the following MACE during follow-up: nonfatal myocardial infarction (n = 1), unstable angina (n = 13), percutaneous coronary intervention (n = 23), and coronary artery bypass grafting (n = 3). No cardiac deaths were recorded.

Patients with at least one 50% or greater stenosis on CCTA images were significantly more likely to experience MACE during follow-up (HR, 2.47; p = 0.0056). This association remained significant after adjustment for age, sex, and clinical risk factors (HR, 2.71; p = 0.0035) (Table 3, Fig. 5). Patients with a perfusion defect in at least one vascular territory at visual analysis of myocardial perfusion CT datasets were at significantly increased risk of MACE (HR, 2.50; p = 0.0040). This association remained significant after adjustment for age, sex, and clinical risk factors (HR, 2.41; p = 0.0064). The adverse prognostic significance of at least one perfusion defect also remained significant after further adjustment for CCTA findings (HR, 2.03; p = 0.0390). The number of territories with perfusion defects was strongly predictive of MACE. The HRs adjusted for age, sex, clinical risk factors, and CCTA findings were 1.41 (p = 0.4378), 3.44 (p = 0.0234), and 4.76 (p = 0.0026) for perfusion defects in one, two, and three territories.