RESPECT2 trial is an investigator-initiated, prospective, community-based, open-label, and pragmatic randomized controlled trial. The primary objective is to assess the effect of the CCTA-guided prevention strategy (CCTA group) on lipid management versus usual care (usual care group) in the asymptomatic population. The second study objective is to determine the prevalence of subclinical CAD among middle-aged and elderly (40 ~ 69 years) asymptomatic community individuals in Nanjing, China. A study flowchart is displayed in Fig. 1.
This study will recruit 40 ~ 69 year-old asymptomatic community individuals in Nanjing, China. Study recruitment will be based on volunteer participation and carried out by investigators. The study will be publicized to targeted groups in community members of 11 municipal districts throughout Nanjing (see S1 in the Supplementary Appendix). The complete trial inclusion and exclusion criteria are shown in Table 1.
Screening will be conducted in 2 steps. First, participants will be enrolled if they meet all general inclusion and exclusion criteria in the form of self-reports and providing written informed consent. Subsequently, the baseline examination will be collected. Second, enrolled participants will be screened again for laboratory index (excluding participants with serious liver dysfunction or eGFR < 30 ml/min/1.73 m2, etc.). The data monitoring committee (DMC) is responsible for generation of allocation sequence. Participants meeting all entry criteria will be then randomly assigned in a 1:1 ratio to the CCTA group or the usual care group, and randomization is stratified by CVD risk stratification (low, moderate, and high risk) which is determined according to the Chinese guideline for lipid management 2023 [20] (Supplemental Fig. 1). In addition, randomization will be generated into blocks, while block sizes will not be revealed to researchers. The randomization sequence will be generated by an independent statistician using the R software version 4.1.2. Although the blinding of participants or clinicians in this study is not possible because the comparator is usual care, the online randomization service will ensure allocation concealment until the participants are recruited into the trial and after all baseline measurements are completed. The primary outcomes will be adjudicated by an independent clinical adjudication committee blind to allocation of intervention. If the participant is assigned to the usual care group, lipid-lowering strategy will be developed based on the CVD risk stratification according to the guideline [20]. If the participant is assigned to the CCTA group, CCTA will be performed first. Then, lipid-lowering strategy will be developed based on CCTA results that indicate the presence or absence of coronary artery plaque. All participants of both groups will receive cardiology clinic counseling and advice. There will be no special criteria for discontinuing or modifying allocated interventions. Besides, implementing CCTA 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. The details of the cardiovascular primary prevention algorithm are described as follows. Firstly, participants will be divided into four categories: apparently healthy participants, the participants with diabetes mellitus, CKD stage 3 (defined as eGFR 30 ~ 59 ml/min/1.73 m2), and severe hyperlipidemia [defined as low-density lipoprotein cholesterol (LDL-C) ≥ 4.9 mmol/L or total cholesterol (TC) ≥ 7.2 mmol/L]. Secondly, four categories of participants will be divided into low risk (< 5%), medium risk (5 ~ 9.9%), or high risk (≥ 10%) degree. Blood pressure control target is set at < 140/90 mmHg and glycosylated hemoglobin A1c (HbA1c) < 7.0% in all subjects. In terms of lipid management, with LDL-C as the control target, the recommended lipid-lowering drug regimen and set target values are as follows (Fig. 2a, b). • Apparently healthy participants. For low-risk population, lipid-lowering drugs will not be recommended, and LDL-C target value is 2.6 mmol/L, and when LDL-C is ≤ 2.6 mmol/L, lipid-lowering drugs will not be recommended; for high-risk population, lipid-lowering drugs will be recommended with LDL-C target values of < 2.6 mmol/L. • Diabetes mellitus (≥ 40 years old). Lipid-lowering drugs will be recommended with LDL-C target values of < 1.8 mmol/L. • CKD stage 3. Lipid-lowering drugs will be recommended with LDL-C target values of < 2.6 mmol/L. • Severe hyperlipidemia. Lipid-lowering drugs will be recommended with LDL-C target values of < 2.6 mmol/L. • Apparently healthy participants. For participants without CAD, lipid-lowering drugs will not be recommended, and the LDL-C target value is < 3.4 mmol/L, while for participants with CAD, lipid-lowering drugs will be recommended with LDL-C target values of < 1.8 mmol/L. • Diabetes mellitus (≥ 40 years old). For participants without CAD and target organ damage, lipid-lowering drugs will be recommended with LDL-C target values < 2.6 mmol/L, while for participants with CAD or combined with target organ damage, lipid-lowering drugs will be recommended with LDL-C target values < 1.8 mmol/L. • CKD stage 3. For participants without CAD, lipid-lowering drugs will be recommended with LDL-C target values < 2.6 mmol/L, while for participants with CAD, lipid-lowering drugs will be recommended with LDL-C target values < 1.8 mmol/L. • Severe hyperlipidemia. For participants without CAD, lipid-lowering drugs will be recommended with LDL-C target values < 2.6 mmol/L, while for participants with CAD, lipid-lowering drugs will be recommended with LDL-C target values < 1.8 mmol/L. In addition, for CAD patients with non-significant coronary stenosis (> 0% and 1.5 mm]), if it is difficult to reduce LDL-C below 1.8 mmol/L, a 50% reduction from baseline will be targeted as an alternative indicator. On the other hand, for CAD patients with significant coronary stenosis (≥ 50% diameter stenosis of any coronary artery [> 1.5 mm]), the lipid lowering goal is to reduce LDL-C to less than 1.8 mmol/L and reduce 50% from baseline. Furthermore, the patients (significant CAD) will receive further intervention from cardiologists, such as aspirin, or even percutaneous coronary intervention.
After randomization and intervention, participants will be followed up at 6 months over phone and 12 months in-person. After that, we plan to conduct annual follow-up (at least 5 years) for the participants. At each visit, data on treatment compliance (see S2 in the Supplementary Appendix), concomitant use of other drugs, onset of cardiovascular or non-cardiovascular events, and occurrence of any other adverse events will be gathered by the investigators. The laboratory tests, including serum lipid, ALT, AST, and creatine kinase will also be collected if available. At the end of the study, all events and adverse events will be reconfirmed for all patients to ensure that case-report forms are accurate.
In order to ensure that participants can be contacted, we will get 4 contact methods at baseline, including the phone number of the participant himself or herself, at least one of the participant’s family members, and the social software, such as WeChat and the medical chain platform. For those participants for whatever reason could not be contacted to assess for primary endpoint data, after documentation of 3 unsuccessful attempts (on 3 different days over a 1-month period) by the follow-up specialists, we will seek help from the staffs in the participant’s community. If all of the above methods fail, the subject will be considered lost to follow-up.
The primary outcome is the proportion of participants taking lipid-lowering medication regularly at both 6 and 12 months. Taking lipid-lowering medication is regularly defined as taking the established lipid-lowering medication (including statin, ezetimibe, Xuezhikang, and PCSK9 inhibitor) at least 24 days during the past 30 days (≥ 80% days) (see S3 in the Supplementary Appendix). To validate outcomes, we will contact participants through social media (i.e., WeChat or medical chain platform) to collect prescriptions, drug packages, and drug payment records. Meanwhile, we will record the follow-up calls as traceable files.
The secondary outcomes are as follows:
• The major secondary outcome: the proportion of participants achieving LDL-C targets at 12 months (the LDL-C treatment goals are made according to Chinese guideline [20])
• Other secondary outcomes: the proportion of participants taking lipid-lowering medication regularly at 12 months; the mean changes in TC and LDL-C from baseline to 12 months; assessing barriers to adherence; safety; changes in renal function following CCTA examination; cardiovascular events; health economics analysis
The study data will be collected at baseline visit and follow-up visits (Table 2). The baseline study examination includes the following: (1) a detailed assessment of self-reported cardiovascular risk factors, including demographic characteristics, medical history, medication use, lifestyle characteristics, and psychosocial factors; (2) physical exams, which include blood pressure, heart rate, height, sitting height, weight, waist circumference, and hip circumference; (3) laboratory tests, such as glucose, glycated hemoglobin, lipids [including TC, LDL-C, HDL-C, lipoprotein(a), etc.], liver and renal function, creatine kinase, homocysteine, high sensitivity C-reactive protein (hsCRP), and routine blood biochemical indexes; (4) this trial involves collecting blood sample for storage; (5) CCTA examination (only for CCTA group). The study data include both eCRF questionnaires and paper-based physical examination indexes (see S4 in the Supplementary Appendix). The data will be collected, coded, and entered to the online EDC system by the trial investigators to ensure that the data would not be tampered. The researchers will be divided into entry and review work to ensure that the data are accurate. To ensure privacy, the data of the participants will be anonymized and each participant will be assigned an ID number to hold personal information and contact details. This will be stored confidentially before, during, and after the trial.
Data on self-reported adherence and adverse events will be collected at each follow-up visit. The detailed assessment of self-reported cardiovascular risk factors, physical exams, and laboratory analyses will be collected again at 12 months (all participants). Self-reported adherence to medications will be recorded as the number of days medication is missed in the month prior to the visit (value between 0 and 30 days). The type and intensity of lipid-lowering drugs will also be documented. Besides, during trial contacts, the research team will record barriers to adherence and reasons for stopping recommended medications for each participant.
Adverse event (AE) monitoring will begin when a participant is randomized and will continue for 1 year. We will record AEs which are defined as serious or which are potentially related to the intervention according to CCTA examination independently. There is no anticipated harm and compensation for trial participation.
CCTA scans will be performed using two 64-detector CT scanners. CCTA protocol optimizations will be performed throughout the study to optimize scanning parameters, such as radiation dose and contrast agent administration. Sublingual glyceryl trinitrate will be administered immediately prior to CT scan. Coronary artery calcium score (CACS) will be performed prior to CCTA according to the standard protocol. CCTA will be conducted using pre-specified protocols during a single breath hold triggered by prospective electrocardiographic gating as appropriate.
All CCTA images will be assessed independently by at least two trained observers referring to the CAD-RADS system [21]. Where there is disagreement between paired observers, CCTA will be reviewed and classified by consensus. All coronary arteries greater than 1.5 mm in diameter will be graded for stenosis severity. Non-CAD is defined as that the coronary arteries have no any visualized plaque and stenosis. CAD will be graded according to the degree of maximal coronary stenosis as (1) minimal stenosis (1–24%), (2) mild stenosis (25–49%), (3) moderate stenosis (50–69%), (4) severe stenosis (a, 70–99% stenosis, or b, left main truck ≥ 50% or 3 major epicardial vessels ≥ 70%), and (5) total coronary occlusion (100%). In this study, obstructive CAD is defined as having ≥ 50% diameter stenosis in at least one major epicardial vessel. Conversely, non-obstructive CAD is defined as encompassing both minimal and mild stenosis.
Based on the reported prevalence and treatment rate of dyslipidemia as well as the 10-year CVD risk levels among Chinese general population [6, 22,23,24,25], we make the following assumptions: after recommendation of lipid-lowering drugs, the highest utilization rate of lipid-lowering drugs is 4 ~ 5% in the control group [the proportion of “medium–high risk” aged 40–69 years in Chinese community is 40 ~ 50%, and the highest utilization rate of recommended lipid-lowering drugs is 10% (4–10%)]. The lowest expected utilization rate of lipid-lowering drugs is 8% after the intervention with CCTA screening (assuming the prevalence of subclinical CAD is 40 ~ 50%, with an expected utilization rate of 20% for those with recommended lipid-lowering drugs). A total of 2836 evaluable participants will be required (1418 per arm) to have 90% power to detect a 3% (8% versus 5%) difference in rates of taking lipid-lowering medication regularly based on two-sided p < 0.05. With a 15% attrition rate, the sample size will be about 3400 participants (1700 per arm). Meanwhile, in order to determine the prevalence of subclinical CAD in the general population, we set the CCTA group in this study as the screening population. Assuming the prevalence of subclinical CAD confirmed by CCTA in an asymptomatic population aged 40 ~ 69 years in Nanjing city is 40 ~ 50% [17,18,19], the tolerated absolute error of 3% with a confidence level of 95%. The sample size calculated should be of 1056 ~ 1098 participants, which is much smaller than the number of participants in the CCTA group above. Confidence interval is calculated using a Z test with a 2-sided significance level of 0.05. The primary analysis will be performed according to intention-to-treat principle. We will also perform sensitivity analyses of the primary and major secondary end points, including per-protocol analysis, as-treated analysis, imputation of missing primary and major secondary endpoint data under the scenarios of worst possible outcome, best possible outcome, and multiple imputation. The intention-to-treat population will consist of participants undergoing randomization. The per-protocol population will consist of participants who will be successfully randomized and undergo the treatment strategy excluding those with major protocol deviations. The as-treated population will consist of participants who will be analyzed according to the actual strategy used for treatment rather than their randomization assignments. Type I error rate will be controlled by use of a hierarchical (fixed-sequence) testing procedure for the primary and major secondary end points, which will be tested in a predefined order (the proportion of participants taking lipid-lowering medication regularly at both 6 and 12 months, the proportion of participants achieving LDL-C lowering targets at 12 months), all at the same significance level alpha (α = 0.05). The modified Poisson regression model with robust error estimation will be used to estimate the risk ratio and 95% confidence interval (CI) associated with treatment effect in the analysis of prespecified primary end point and other dichotomous end points, with adjustment for prespecified covariates. Mean changes in TC and LDL-C levels from baseline to 12 months will be analyzed using linear regression models. Plots of the cumulative incidence curves for cardiovascular events will be provided using Kaplan–Meier estimates. Estimates of the hazard ratios and 95% CI of cardiovascular events will be calculated using a Cox proportional hazards model. These models will be adjusted for stratification variables. Subclinical CAD prevalence will be estimated using the Wald method and corresponding 95% CIs are provided. For all primary analyses, 2-sided P values less than 0.05 will indicate statistical significance. Because of the potential for type I errors due to multiple comparisons, the findings from the analyses of secondary outcomes will be interpreted as exploratory. All statistical analyses will be performed using the SAS software, version 9.4 (SAS Institute), by independent statisticians masked in the allocation of the treatment group. The study is an investigator-initiated, institutionally sponsored study, and therefore, the authors are solely responsible for the design and conduct of this study as well as data analysis and drafting of publications. The steering committee (SC) is the main decision-making committee of the trial and has final responsibility for the medical and scientific conduct of the trial. The clinical events committee (CEC) is responsible for adjudicating all primary and secondary endpoints and consists of 2 experienced cardiologists, 1 experienced neurologist, 1 radiologist, and 1 statistician. The DMC includes cardiologists and statisticians. The DMC will regularly monitor the safety of the subjects enrolled in the study. Based on their clinical judgment, the DMC can recommend stopping the trial. No members of the CEC or DMC will participate in recruitment or data collection. The sponsor will not play any part in the study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. In addition, data collected during the course of the research will be kept strictly confidential and only accessed by members of the trial team. At present, there is no plan to share the data with other teams or organizations. The datasets analyzed during the current study will be 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. The study will designate researchers, for example, JJ and RZ to obtain informed consent and formally recruit. On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. This trial will involve collecting blood sample for storage. Informed consent forms will be available from the corresponding author on request. If it is necessary to amend protocol, we will notify the sponsor and funder. 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 will be conducted in accordance with the ethical principles of the Declaration of Helsinki (2013) and Good Clinical Practice for Medical Devices (GCP, 2016). The study protocol, the written informed consent form, and other relevant documentation have been approved by the institutional ethics committee. It is the responsibility of the sponsor (the study PI) to ensure that written informed consent is obtained and to report serious adverse events occurring during the study to the institutional ethics committee at Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University. Informed consent materials will be available upon request from the principal investigator. All study members will be well trained by standard operation procedures.…Read more by Liu, Beijing, Ying, Jinling Hospital, Affiliated Hospital of Medical School, Chao, Nanjing Medical University, Yang, Xuzhou Medical University, Wu, Ma, Jian, Bingqian, Jianhua, Yingqi, Nanjing University of Chinese Medicine, Statistics Division of Department of Critical Care Medcine, Zhao, Jinwei, Department of Radiology, Long Jiang, China, Jingzhou, Pengfei, Cai, Nanjing, Xiang, Response, Zhong, Chen, Tian, Di, Epidemic Preparedness, Department of Cardiology, Zhou, Peking University, Xiaoqing, Xu, Jinling School of Clinical Medicine, Junqing, Xinran, Center for Public Health, Bao, Yi, Haowen, Yuting, Zuo, School of Medical Imaging, Yuxiu, Nanjing University, Jiang, Sun, Yongyue, Dongna, Gong, Yanming, Jun, Li, Xuzhou, Data, Conghong, Jialuo, Wei, Cheng, Guo, Zhu, Rui, Zhang, Xueqin, Minjie, Changsheng, Wang
