These two authors contributed equally to this study.
Chest pain is one of the most common complaints in the emergency department (ED). Cardiac computed tomography angiography (CCTA) is a frequently used tool for the early triage of patients with low- to intermediate-risk acute chest pain. We present a study protocol for a multicenter prospective randomized controlled clinical trial testing the hypothesis that a low-dose CCTA protocol using prospective electrocardiogram (ECG)-triggering and limited-scan range can provide sufficient diagnostic safety for early triage of patients with acute chest pain.
The trial will include 681 younger adult (aged 20 to 55) patients visiting EDs of three academic hospitals for acute chest pain or equivalent symptoms who require further evaluation to rule out acute coronary syndrome. Participants will be randomly allocated to either low-dose or conventional CCTA protocol at a 2:1 ratio. The low-dose group will undergo CCTA with prospective ECG-triggering and restricted scan range from sub-carina to heart base. The conventional protocol group will undergo CCTA with retrospective ECG-gating covering the entire chest. Patient disposition is determined based on computed tomography findings and clinical progression and all patients are followed for a month. The primary objective is to prove that the chance of experiencing any hard event within 30 days after a negative low-dose CCTA is less than 1%. The secondary objectives are comparisons of the amount of radiation exposure, ED length of stay and overall cost.
Our low-dose protocol is readily applicable to current multi-detector computed tomography devices. If this study proves its safety and efficacy, dose-reduction without purchasing of expensive newer devices would be possible.
It is unknown whether a low-dose cardiac computed tomography angiography strategy using prospective gating and limited scan range can provide clinically sufficient diagnostic safety in emergency department patients with acute chest pain.
We present a study protocol to test a hypothesis that a low-dose cardiac computed tomography angiography protocol using prospective electrocardiogram-triggering and limited-scan range can provide sufficient diagnostic safety for early triage of patients with acute chest pain.
Chest pain is one of the most common complaints in the emergency department (ED) with an annual visit of eight to ten million patients in Unites States [
However, such practice has been criticized for causing unnecessary radiation exposure [
We believe this is due to the lack of prospective clinical trials that have proven the diagnostic safety of a low-dose CCTA protocol, especially in a real ED situation. We hypothesized that a low-dose CCTA protocol with prospective ECG-triggering and limited-scan range, which are readily applicable to most 64 or higher channel multi-detector CT imagers, can provide sufficient diagnostic safety for early triage of patients with acute chest pain. We initiated a multicenter prospective randomized controlled clinical trial assessing its diagnostic safety and other important aspects (radiation dose, ED length of stay, and cost). This report provides a comprehensive summary of our study design and several practical issues raised so far.
The study is a prospective, randomized, controlled, multi-center trial comparing a low-dose CCTA protocol using prospective electrocardiogram (ECG)-triggering and limited scan range with a conventional imaging protocol for early triage of low-to-intermediate-risk patients presenting to the ED with acute chest pain. The primary objective is to prove that the chance of experiencing any hard event (cardiac death or myocardial infarction) within 30 days after a negative low-dose CCTA test is less than 1% [
Three academic hospitals in South Korea are participating in this trial. Sites 1 and 3 are located in Seoul metropolitan city with annual ED visit of over 100,000 and 45,000, respectively. Site 2 is located in Seongnam city with over 80,000 annual ED visits. All the three hospitals are capable of emergency percutaneous coronary intervention on a full-time basis.
This study was reviewed and approved by the institutional review boards of all participating hospitals (SNUBH IRB no. B-1211/177-005). Informed consent is absolutely required for study participation. This study was registered on December 20 2012 under ClinicalTrials.gov number NCT 01770444 and patient enrollment was first started in June 21 2013.
Adult patients aged 20 to 55 with acute chest pain or equivalent symptoms requiring further evaluation to rule out ACS are eligible to participate in this trial. The decision for enrollment is made by treating physicians after an initial evaluation that includes ECG, chest PA and cardiac bio-marker and D-dimer tests. Older (aged >55) patients are excluded because the harmful cumulative effect of radiation exposure from a CCTA test would relatively be small in this population [
Eligible patients signing informed consent are provided with a colored wrist band for better recognition by researchers and ED/radiology staff. As prospective ECG triggering requires rather strict control of heart rate (HR) [
The detailed description of the imaging protocol is in
Image interpretation is provided by cardiac imaging specialists. The distribution, severity and characteristics of observed coronary lesions and other clinically relevant non-coronary abnormalities are reported if there are any.
Patient ED disposition is determined by both CT findings and clinical progression in ED. Basically, patients with no high-risk findings in their CCTA images as defined in
Baseline characteristics including demographic information, thrombolysis in myocardial infarction risk score, Canadian Cardiovascular Society angina grading scale and Killip class are collected at the time of enrollment. Similarly, the results of serial ECGs and cardiac biomarker tests (creatinine kinase-MB and troponin I) as well as CCTA imaging are also collected as soon as their results are reported. The clinical course during the first month after discharge is assessed from the patients or their surrogates via a telephone interview. They are asked about whether there were additional functional or imaging tests (e.g., treadmill test, myocardial perfusion imaging, cardiac positron emission tomography, invasive coronary angiography), unstable angina, myocardial infarction, cardiac arrest, hospital admission or revascularization. If there were any, detailed descriptions of the event(s) are obtained from the contacted person and the hospital(s) involved. If the patients or their surrogates could not be contacted, hospitals located nearby the house of the patient are asked whether the patient visited them for any related problems. In cases where all the above measures fail, the Korean National Statistical Office is contacted whether the patient was reported to be deceased.
The primary objective of this trial is to determine whether the chance of having a hard event (myocardial infarction or death) within the first month after negative low-dose CCTA result is less than 1%. The secondary objectives are to compare the diagnostic accuracy, incidence of major adverse cardiac events within one month after discharge, overall radiation exposure, ED length of stay and overall cost between the two groups.
The primary endpoint of this study is to test the hypothesis that the chance of having a hard event within one month after negative CCTA is less than 1%. Based on the pooled results of previous studies, we assumed that the chance of having a hard event in patients without significant (≥50%) coronary stenosis is about 0.576 [
Participants will be randomly allocated to either low-dose or conventional CCTA protocol in a 2:1 ratio. The randomization procedure is confidential. Each study participant is allocated to either low-dose or conventional CCTA protocol in the CT room by opening the next sequential sealed opaque envelope containing the next assignment. The randomization process and the preparation and distribution of the sealed envelopes were done at site 2. This is a single blind study in which only participating patients are blinded to their assigned protocol. This is because of the obvious difference in scan range which makes it impossible to blind the treating physicians and radiologists to the allocation.
The primary hypothesis will be accepted if the upper bound of the one-sided 95% confidence interval of false negative rate lies below the predetermined safety margin of 1% missing rate. For secondary outcomes, both intention-to-treat analysis and additional per-protocol analysis will be carried out. Student’s t-test, Mann-Whitney U-test, chi-square test, and Fisher’s exact test will be performed for comparisons as appropriate for the nature of the variables being compared. P-values <0.05 will be considered significant. All analyses will be performed using STATA ver. 12 (StataCorp., College Station, TX, USA).
Radiation exposure from CCTA can be reduced by altering one of three elements; exposure duration, scan range and radiation density. Our low-dose protocol using prospective gating and limited scan range can minimize the exposure duration and scan range. However, these modifications have their own requirements or shortcomings which might impede their nationwide implementation. To facilitate the process, the following interventions can be applied.
Prospective gating requires strict control of heart rate and its variability [
ACS is not the only source of acute chest pain which can lead to serious consequences. One of the great advantages of CCTA is its ability to rule out dangerous non-coronary etiologies of chest pain such as aortic dissection and pulmonary embolism. Though low-dose CCTA protocol does cover the thorax under carina, there is a possibility of missed aortic dissection or pulmonary embolism. Therefore, patients with an unlikely clinical probability of pulmonary embolism and a normal D-dimer level are included in this study [
No potential conflict of interest relevant to this article was reported.
This research has been supported by research grants from SK Telecom (06-2013-102) and the National Strategic Coordinating Center for Clinical Research (HI10V-0078-010014).
HR control protocols
Facility | Oral beta-blockers dosing regimen | Intravenous beta-blockers dosing regimen |
---|---|---|
Site 1 | Bisoprolol tablet | Esmolol bolus over 1 minute |
HR >90 bpm: 2.5 mg |
HR 65–80 bpm: 1 mg/kg | |
HR >80 bpm: 2 mg/kg (up to 3 times or 3 mg/kg) | ||
Site 2 | Oral metoprolol tablet | Esmolol bolus over 1 minute |
HR 65–70 bpm: 50 mg | HR 65–70 bpm: 0.5 mg/kg×0.7 | |
HR >70 bpm: 100 mg | HR 70–90 bpm: 0.5 mg/kg | |
HR >90 bpm or body weight >90 kg: consider 150 mg | HR >90 bpm: 0.5 mg/kg×1.3 (up to 3 times or 2 mg/kg) | |
Site 3 | Same as site 2 | Same as site 2 |
HR, heart rate.
Patients with heart rate >65 and ≤90 bpm are administered with intravenous esmolol in computed tomography room if required.
Cardiac computed tomography angiography protocols
Protocol | Gating | Scan range | Heart motion assessment | Estimated radiation dose |
---|---|---|---|---|
Conventional CCTA | Restrospective |
Clavicle to heart base | Available | 10 mSv |
Low-dose CCTA | Prospective | Sub-carina to heart base | Not available | 4.5 mSv |
CCTA, cardiac computed tomography angiography.
With tube current modulation.
High-risk image and clinical findings
High-risk image finding | High-risk clinical finding |
---|---|
Significant coronary artery stenosis (≥ 50%) | Dynamic ST-T change |
Regional wall motion abnormality |
Increasing biomarkers |
Perfusion defect | Ongoing chest pain or dyspnea |
Non-coronary high-risk findings (e.g., pulmonary embolism, aortic dissection, pneumothorax, severe pneumonia) | Other high-risk findings (e.g., ventricular arrhythmia, high-degree block, syncope, desaturation or shock) |
Regional wall motion assessment is only available in conventional protocol group.