The study included patients aged ≥ 18 years who were referred for ICA based on clinical suspicion of de novo CAD and an abnormal NIST.
Patients with uncontrolled severe angina, acute coronary syndromes, previously known CAD, atrial fibrillation, inability to obtain a steady sinus rhythm, chronic kidney disease or previous kidney transplantation, contrast allergy, or other CCTA-specific contraindications were excluded. Patients with an abnormal NIST classified as severe or reported as inconclusive were also excluded. All other NIST abnormalities were accepted as mild or moderate. Ischemia severity was determined by an NIST reading and/or referring physicians and was not adjudicated by investigators. Detailed patient selection criteria are listed in Table 1.
We conducted a prospective, open-label, randomized controlled trial in a single academic tertiary center between January 2015 and December 2018, to compare the diagnostic yield of ICA (detection of obstructive CAD) from two different patient selection strategies.
Patients were recruited after referral to ICA and were only included in the study if the attending physician consented. The randomization process used a computer-generated sequentially numbered list. Investigators and participants were blinded to the randomization sequence but not to the assigned group. In the conventional ICA strategy, patients were allocated to undergo ICA, as originally intended. In the selective strategy, patients were allocated to undergo CCTA, and the results were made available to the patients and referring physician. The final decision on whether to proceed or not with ICA was taken by the attending clinician. Investigators did not intervene in clinical management.
All patients were followed-up by telephone interviews and clinical chart reviews for at least 12 months after undergoing CCTA or index ICA, whichever occurred later.
The investigation conforms to the principles outlined in the Declaration of Helsinki. The institutional ethics committee approved the study protocol. All patients provided written informed consent for participation in the study according to the standards approved by the local ethics committee.
Baseline data and non-invasive ischemia tests
Baseline data on demographic, clinical, and symptomatic status were recorded, including data on cardiovascular risk scores (Framingham and European SCORE) (9, 10). The pre-test probability of obstructive CAD was determined per the Duke clinical score (11).
Cardiac computed tomography angiography, invasive coronary angiography, and revascularization
CCTA was performed following the selective arm strategy. From January 2015 to May 2016 a 64-detector computed tomography (CT) scanner (VCT 64 Lightspeed, GE healthcare, Wisconsin, USA) was used. Thereafter, the exams were performed on a dual-source 128-detector CT scanner (Somatom Definition Flash, Siemens, Erlangen, Germany). Acquisition protocols, interpretation, and reporting were performed according to local standardized practice. Coronary calcium quantification and classification per the Agatston method were carried out in all cases (12). The investigators classified the CCTA results as “negative” (in the case of normal coronary arteries or nonobstructive CAD) or “positive” (in the presence of obstructive CAD defined as at least one segment with stenosis ≥ 70%, left main stenosis ≥ 50%, high calcium score precluding CT angiogram as determined by the attending imager or by the presence of any uninterpretable segment) (13).
Regardless of the randomization group, when the referring clinician decided to proceed to ICA, it was performed within a period not exceeding 3 months after randomization. The ICA was performed per the current institutional standards by operators who were not involved in the study. Obstructive CAD was defined as stenosis in ≥ 50% of the left main coronary artery or stenosis in ≥ 70% in any coronary vessel with at least 1.5 mm diameter. A normal coronary artery was defined as the complete absence of any luminal narrowing detectable by angiography. Nonobstructive CAD was defined as CAD not meeting the criteria for obstructive CAD or normal coronary arteries.
After undergoing diagnostic ICA, the decision to proceed with revascularization or not (percutaneous or surgical) for each patient was taken by the attending cardiologist and interventional operator and was not conditioned by any protocol specification of the study.
The primary endpoint of the study was the ICA diagnostic yield, which was defined as the proportion of patients with obstructive coronary disease in each arm as determined by ICA.
1. Rates of ICA in the patients randomized to the group of selective ICA. To determine if a stratification strategy that included CCTA applied to a population with stable CAD and abnormal NIST could decrease referrals for ICA. This pre-specified secondary endpoint was reached if the referral rate for ICA in the selective group was at least 40% lower than that in the control group.
2. Revascularization yield (percutaneous or surgical). To determine whether the use of CCTA in the selective strategy ultimately led to higher rates of revascularization (proportion of revascularized patients with respect to the total number of patients undergoing ICA).
3. Any major adverse cardiovascular events 12 months after randomization. A combined endpoint that includes all-cause death, non-fatal myocardial infarction, unstable angina (angina recurring or requiring hospitalization, urgent revascularization), non-fatal stroke, or cardiovascular hospitalization.
4. Mean cumulative radiation exposure in each group. We assessed the overall radiation exposure (in millisieverts) using the dose-length product (converted using factors of 0.014 mSv/mGy×cm) for CT and modeled radiation and published survey data for ICA, percutaneous coronary intervention, and myocardial perfusion imaging (7 mSv, 15 mSv, and 14 mSv, respectively) (14).
5. Mean cumulative contrast dose in each group. Contrast used in CCTA, ICA, and percutaneous coronary intervention, when performed, was included.
The study tested the following null hypothesis (H0), π1 (primary endpoints in the selective strategy)=π2 (primary endpoints in the direct strategy), and an alternative hypothesis (H1), π1 (primary endpoint in the selective strategy) ≠ π2 (primary endpoints in the direct strategy), using the bilateral χ2 test for a significance level of 0.05, power of 0.8, and a risk of occurrence of the first primary endpoint (obstructive CAD on ICA) of 50% in the direct ICA strategy, and 80% on the selective ICA. This estimate is based on the expected prevalence of obstructive CAD of 50% (15) and negative predictive value of CCTA > 90% described in the literature (16). We estimated that a sample of 120 individuals in each study arm would be needed to verify a reduction in the normalcy rate of ICA from 50–20%, with 95% confidence, and 80% potency.
Continuous data were assessed using the unpaired t-test or Mann-Whitney test, and categorical data were assessed by χ2 or Fisher tests, as appropriate. Normally distributed continuous variables are expressed as mean ± SD, and non-normally distributed data are expressed as medians and interquartile ranges. All data were analyzed using SPSS 20.0 (IBM, NY, USA).