TARGET trial is a multicenter, prospective, open-label and pragmatic randomized controlled trial evaluating the effect of a CCTA/CT-FFR strategy (Group A) on management decision making versus usual care (Group B) in intermediate-to-high risk patients with suspected CAD who undergo clinically indicated diagnostic evaluation.
Recruitment commenced in August 2019. Additional file 1 is the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. The schedule of enrollment and assessments follows the SPIRIT Figure. The study protocol (Version 2.0/201812) and other relevant documentation have been approved by the institutional human research ethic committee of Chinese PLA General Hospital and the relevant national ethics committees as well as registered on ClinicalTrials.gov identifier: NCT03901326.
This multicenter randomized controlled clinical trial will be carried out in 6 tertiary hospitals across China, all of which has the volume of over 200 patients in out-patient area of cardiology division each working day. Participating subjects will be enrolled and subsequently assigned to either usual care group or CT-FFR care group via computer-generated random numbers (1:1 ratio) (Figure.1). The trial accords with SPIRIT guidelines. Core lab has been established to receive all the imaging data for analysis, and two trained clinicians will conduct all of the measurements. The treatments (both intervention and control) will be delivered by licensed clinicians in the participating sites. Central telephone is used for allocation of sequence. Participants will be randomized to the CT-FFR examination group or usual care group using a randomization procedure. The cardiologist will be aware of patients’ group allocation because they will provide the trial intervention, but they will not be involved in the analysis. Participants are not blind to their group allocation, nor are their physicians who are informed of screening results of their patients (if the patient consent) and give the recommendation by outpatient or telephone. There will be no special criteria for discontinuing or modifying allocated interventions.
Consecutive patients with new onset chest pain suspicious for CAD will be included. Subjects with intermediate-to-high likelihood of CAD will be recruited based on various typicality of chest pain. Another major inclusion criterion is the CCTA result which showed that the diameter stenosis is between 30% and 90% in at least one major coronary artery (coronary artery diameter≥ 2.5 mm).
The typicality of the chest pain were determined by three characteristics of chest pain, including central chest discomfort lasting below 15 minutes, provoked by exertion or emotional stress, and relieved by rest or nitrates. This definition is similar with The NICE guideline update (2016). Non-anginal pain was defined as the presence or absence of only one characteristic of chest pain. Atypical angina was defined as the presence of two characteristic. Typical angina was defined as the presence of all three characteristic above. For the mild coronary stenosis (30-49%), patients with typical angina will be recruited. For the intermediate stenosis (50-69%), patients with atypical angina or non-anginal pain will be recruited. For the severe stenosis (70-90%), only patients with non-anginal pain will be included.
Agreement to participate in this trial will be necessary and informed consents will be obtained from all subjects before recruiting.
- Diagnosed or suspected acute coronary syndrome requiring hospitalization or emergent testing;
- Hemodynamically or clinically unstable condition systolic blood pressure < 90 mmHg or serious atrial or ventricular arrhythmias;
- Known CAD with prior myocardial infarction, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or any angiographic evidence of ≥50% stenosis in any major coronary artery;
- Patients with left main branch stenosis>50% and/or 3-vessel disease;
- Known severe congenital, valvular (moderate and above) or cardiomyopathy process (hypertrophic cardiomyopathy or reduced systolic left ventricular function ≤ 40%) which could explain cardiac symptoms;
- Unable to provide written informed consent or participate in long-term follow-up.
CCTA image is obtained before the patient’s first visit and assessement. When subjects are randomized to the CCTA/CT-FFR arm, on-site FFR based on the CCTA imaging (DeepFFR V1.0.0, Beijing CuraCloud Technology Co., Ltd., Beijing, China) will be measured. DeepFFR workstation is very dedicated software utilizing the original CCTA imaging to meter simulated FFR values in artificial intelligence (AI) model, which has been introduced in previous article. The calculation process could be summarized as follows: The first step is to extract a 3D coronary artery model and generate coronary centerlines which are similar to the routine reconstruction of CCTA. A modified 3D U-Net like model is employed to generate a major coronary artery tree followed by a graph-cut to refine the boundary of the arteries. The centerlines are extracted using a minimal path extraction filter. Then a novel path-based deep learning model, referred to DeepFFR, is used to predict the simulated FFR values on the vascular centerlines. Deep learning algorithm is used to establish characteristic sample database of coronary hemodynamics characteristic parameters. When deep training model is proved to be valid, it is applied to a new lesion-specific measurement. DeepFFR system consists of a multi-layer perceptron network (MLP) and a bidirectional multi-layer recursive neural network (BRNN). The whole model can process variable-length input, and each point of the input sequence is transferred separately corresponding to MLP, output of the MLP is transferred into the BRNN to optimize the sequence model. In comparison with the previous technology, the major advantage of DeepFFR model is more accurate because of the incorporation of context information on target FFR along the vessel path. More specifically, DeepFFR workstation includes the neural networks set on each point of the vascular path. Structural and functional features of each point on the vascular centerlines is considered as input, while calculating FFR of each point as output. Therefore, DeepFFR on the coronary tree simultaneously at a quickly time at post processing (Figure.2). Lesion-specific CT-FFR is defined as simulated FFR value at distance of 20 mm away from lesion of interest.
If the subjects are randomly allocated to CCTA/CT-FFR arm, they will be examined by DeepFFR for three major epicardial arteries. If the result of CT-FFR calculation is less than or equal to 0.8 in one or more major coronary arteries, the patient will be referred to ICA directly; if the result of CT-FFR value is more than 0.8, optimal medical therapy will be recommended. The decision on the mode of revascularization is left to the treating cardiologists and depends on local practice.
Correspondingly, if the subjects are randomized to usual care arm, attending physicians will decide next step of diagnosis and treatment, such as exercise ECG, stress cardiac echo, cardiac MR and SPECT. According to the results of examination combined with risk factors assessment and clinical manifestations, physicians should provide recommendation whether the subjects would undergo ICA or not.
The evaluation criteria of functional examination include but not all:
- The exercise ECG criterion for a positive test is greater ≥1 mm of horizontal or down sloping ST-segment deviation (depression or elevation) in any lead except aVR for at least 60 to 80 ms after the end of the QRS complex, either during or after exercise;
- The nuclear cardiology criterion for a positive result is evaluated as: Perfusion is graded using a 5-point scale (0 to 4) in each of 20 myocardial segments. Summed rest scores, summed stress scores, and summed difference scores (SDS) are recorded. Reversible defects are graded as small if SDS was 2 to 4; moderate if SDS was 5 to 8; or large if SDS was >8. Subjects are categorized as having ischemia if more than 1 of the following criteria was present: SDS was ≥2 and/or there was an ungated stress-and-rest volume (transitory ischemic dilation) ratio of >1.19;
- The stress cardiac echo criterion for a positive result is evaluated as: Abnormal findings include those with fixed wall-motion abnormalities or new or worsening abnormalities indicative of ischemia. A segment with resting dysfunction may show either a sustained improvement during stress indicating a non-jeopardized myocardium (stunned) or improve during early stress with subsequent deterioration at peak (biphasic response). The biphasic response is suggestive of viability and ischemia, with jeopardized myocardium fed by a critically coronary stenosis. Resting wall-motion abnormalities, unchanged with stress, are classified as “fixed” and most often represent regions of prior infarction.
The DICOM imaging data will be transferred to on-site workstation to complete DeepFFR measurement and the on-site lab will provide the report to the referral physician within 24 hours for decision making.
On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the hospital taking part in the research, where relevant. This trial does not involve collecting biological specimens for storage.
Downstream decision making
The results of the index test will be provided to the reference cardiologist of the patients' institution who will make clinical decisions based on the integrated evaluation of patient clinical assessment and index test findings. The following downstream decision making will be recorded from study entry until the end of follow-up:  non-invasive diagnostic tests, including further stress testing (exercise or pharmacological stress), with detection of ischemia by ECG, myocardial perfusion, or wall motion abnormalities;  number of ICA and prevalence of non-obstructive CAD at ICA;  Goals of risk factors control by optimal medical therapy.
At baseline, 6 months and 12 months recommendations for therapy are made in line with guidelines published. The goal of anti-hypertensive therapy is to achieve a blood pressure of less than 140/90 mmHg. The choice of anti-hypertensive therapy will be left to the treating physician. The aim of anti-lipid therapy is to achieve levels of LDL < 1.9 mmol/l. In the first instance, statin therapy will be initiated and then increased with the addition of a second agent if necessary. In the case of diabetics with a raised blood sugar, the primary health care physician is asked to measure HbA1c and to ensure that the patients’ subsequent therapy is tailored to achieve a HbA1c of less than 6.5 mg/dl. Smokers are referred to the smoking cessation clinic.
Data monitoring committee is responsible for generation of allocation sequence, and the investigators of each sub-center is responsible for enrollment of subjects. After randomization, participants in CT-FFR group will be assigned to receive CT-FFR examination according to the clinical physicians. The investigators will not take part in the recommendation of usual care for participants. Implementing CT-FFR or usual care will not require alteration to usual care pathways (including use of any medication) and these will be permitted to continue for both trial arms.
Subjects will be contacted regularly by trained interviewers at 90 days, 6 months and 12 months post-enrollment for follow-up assessment until death, withdrawal or end of the trial. All subjects are followed for a minimum of 12 months. An independent clinical events adjudication committee (CEC) reviewed all primary endpoint event and secondary endpoints in a blinded fashion. The decisions of CEC will be used to implement the final statistical analysis.
The data were collected, coded and entered by the trial investigators, and the paper-based CRFs form is sent to trial office by investigators to ensure that the data would not be tampered with. The researchers used double data entry, range checks for data values method to ensure the accuracy of the data. A Clinical Research Organization (CRO) has been contracted to oversee the monitoring of all sites, establishing the eCRF and checking the completeness and consistency of the trial data. Adherence to this trial will be monitored via hospital information system. The follow-up examination results should be sent to the research site, and the examination results of grade-three hospital can be accepted to maintain the credibility.
Endpoint of the study
The primary endpoint of the present trial is comparison between the two arms in the rate of planned ICA without significant obstructive CAD within 90 days. Significant obstructive CAD is defined as more than or equal to 70% of area stenosis by quantitative analysis in core lab or invasive FFR≤0.8 if available during procedure.
The secondary endpoint will be the comparison between the two treatment arms in terms of MACE, quality of life, cumulative effect dose of radiation exposure and overall medical cost during the follow-up at 1 year.
The Seattle Angina Questionnaire (SAQ) was used to assess the clinical effect and quality of life (QOL). We will also measure the cumulative radiation exposure dose (ED) over the entire study period by assessing the original average dose for each test performed during the follow-up. In case the ED for each test is not known, we will use the standard ED available for each test in the literature.
Major adverse cardiovascular events (MACE) will be defined as a combined endpoint of: a) hospitalization for unstable angina; b) revascularization by PCI or CABG after 90 days; c) non-fatal MI; e) cardiac death: any death because of immediate cardiac cause (e.g., MI, low-output failure, fatal arrhythmia) or vascular cause (e.g., cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause). Unwitnessed death and death of unknown cause will be classified as cardiovascular death. An independent clinical events adjudication committee will review the agreement between all events and the provided definitions.
Adverse events (AEs) monitoring will begin when a participant has been randomized and will continue for 1year. We will record AEs which are defined as serious or which are potentially related to the intervention according to CT-FFR result independently. Since we defined MACE as secondary endpoint, so the SAEs (including death, cardiac events, hospitalization for unstable angina pectoris) is a part of study. There is no anticipated harm and compensation for trial participation.
Sample size calculation
The sample size is defined based on the rate of planned ICA without significant obstructive CAD within 90 days. Based on previous data and assuming the prevalence of non-obstructive CAD during ICA in usual care group is about 30%. The frequency of reduction in the primary endpoint is expected to be 30% for a ≥90% power. Considering a drop-off up to 10%, the final overall population should be of 1216 patients.
All data statistical analysis will be performed using Stata version 15.0 (StataCorp, College Station, Texas). The distributions [mean ± standard deviation (SD)] of the parameters are calculated. The parameters are compared between the groups using either Student’s t test for paired or Wilcoxon test for non-paired samples. The Chi square test is applied for the comparison of categorical variables. Multivariable regression or logistic regression is used for analysis of association of various parameters. Cox multivariable regression model is used to find the causal inference between clinical pathway and accordingly endpoints. The hazard ratio (HR) is presented as 95% confidence intervals (CI). P<0.05 is considered as significance in statistics. Because there are no anticipated problems that are detrimental to the participants, interim analyses and formal stopping procedure are not necessary for this trial. Missing values will be managed by using multiple imputation. If there is any non-adherence with the trial protocol and intervention plan, investigators will record it truthfully. TSC will confirm whether there is a major protocol deviation and whether it can be used for data analysis. Intention-to-treat analysis will be applied for patients who do not adhere to the intervention. Based on the data of the current study, further subgroup analysis will be conducted for the additional purpose in the future.
Date management and organization
In order to ensure and monitor the progress of TARGET registry trial, Trial Steering Committee (TSC) has been established including the the authors of this study. As the principal investigators, YC and JY are responsible for co-leading the study. They will ensure the integrity and standardization of the study by managing and supervising the study activities and report of finding as a whole. They will facilitate closely with the sub-center, by initiating and maintaining communication among the study staff of six sub-center, meeting with the faculty investigators every month, and providing continuous supervision and support. DS, ZW, MD, XM, XH and HZ, as the investigators of sub-center, are mainly responsible for identifying potential recruitment and taking consensus. One data collector will be based at each sub-center, and will be responsible for recruiting participants and obtaining data through regular interviews. The data management team, led by JY, will be responsible for the storage, analysis and interpretation of quantitative data. The team will clean up the data and code measures at each point in time to ensure that the data is valid and easy to be interpreted. The sponsor played no part in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.
Data collected during the course of the research will be kept strictly confidential and only accessed by members of the trial team (or individuals from the Sponsor organisation or centre sites where relevant to the trial). On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the hospital taking part in the research, where relevant. This trial does not involve collecting biological specimens for storage. At present, there is no plan to share the data with other teams or organizations. The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Results will be disseminated via a peer-reviewed report to the sponsor, which will be freely available, and through open access journal articles and conference presentations. Standard journal authorship criteria will apply; there will be no use of professional writers.
Informed consent forms are available from the corresponding author on request. If it is necessary to amend protocol, we will notify sponsor and funder first then the primary investigator will notify the centers and that a copy of the revised protocol will be sent to the primary investigator to add to the Investigator Site File. Any deviations from the protocol will be fully documented using a breach report form and the amendment of protocol will be updated in the clinical trial registry.
The study protocol is complied with the World Medical Association Declaration of Helsinki. Ethical clearance for the TARGET trial has been obtained from the ethical committee of Chinese PLA general hospital.