Trial of Cardiac CT in Acute Chest Patients With Intermediate Level Initial High-sensitivity Cardiac Troponin
Trial of Cardiac CT in Acute Chest Patients With Intermediate Level Initial High-sensitivity Cardiac Troponin
Patients who present to the emergency department (ED) with acute chest pain (ACP) possibly
 due to Coronary artery disease (CAD), with a normal heart tracing (ECG), need to have further
 troponin blood tests to confirm or exclude a heart attack. After initial troponin testing, a
 significant 50-85% of patients are said to be in an "observational zone" as one cannot
 confirm or exclude a diagnosis of a heart attack. Even after repeat blood testing, 22-33%
 remain in this "observational zone". These patients can be challenging to manage as they are
 not safe to be discharged home, but they also cannot be treated as a heart attack. This
 contributes to ED overcrowding and uncertainty in treatment plans.
1. Background Coronary artery disease (CAD) remains the most common cause of mortality in the
 world according to the World Health Organisation (WHO). Chest pain accounts for a significant
 healthcare burden representing approximately 700,000 annual visits to the emergency
 department in England and Wales [1]. Patients with acute chest pain (ACP) of possible cardiac
 origin account for approximately 17% of all emergency department (ED) consultations, but less
 than 10% of these are eventually diagnosed with acute myocardial infarction (AMI).

 Hence a means of evaluating these patients in the ED in an efficient manner, whilst ensuring
 high sensitivity and specificity, is of paramount importance. Cardiac biomarkers e.g. cardiac
 Troponin (cTn) I or T along with electrocardiogram (ECG) remain the cornerstone in the
 evaluation of patients with suspected acute coronary syndrome (ACS).

 1.1 Performance of high-sensitivity cardiac troponins High-sensitivity cardiac troponin
 (hs-cTn) assays enable the measurement of cTn at concentrations not detected with the former
 generation conventional cTn assays. In September 2015 hs-cTn assays were adopted in the
 European Society of Cardiology (ESC) guidelines for the management of patients with acute
 coronary syndrome (ACS) without persistent ST elevation. The proposed algorithms advocate
 either a single hs-cTn at ED presentation or repeat measurements after 1 or 2 hours thus
 enabling a more rapid "rule-in" and "rule out" of AMI compared with conventional cTn assays.
 The cut off values for the different hs-cTn assays are assay specific [2].

 The performance of these algorithms (involving hs-cTn) has been evaluated in multiple
 studies. A prospective multicentre study by Gimenez et al looked at ruling out AMI using
 undetectable levels of hs-cTn (I and T) at presentation. With hs-cTnT, AMI was ruled out in
 26.5% of cases with a negative predictive value (NPV) of 98.6%. Among three different hs-cTnI
 assays which were studied, the NPV ranged from 98.8% to 100%. No patient with undetectable
 levels of hs-cTnT died during the first 30 days and only 0.4% had died (2 patients not due to
 AMI) at 24 months' follow-up. Among the three hsc-TnI assays, mortality at 24 months ranged
 from 0 to 2.4% with only one death due to AMI (which occurred in the first 30 days) [3].

 Although the more rapid risk-stratification with these algorithms (on the first sample of
 hs-cTn) helps in reduced time to rule-in or rule-out AMI there remains, however, (between the
 initial "rule-in" and "rule-out" categories) an intermediate "observational zone" category of
 patients, who do require a serial troponin test at 1 hour for further risk-stratification.
 Recent pilot data by Marjot et al have shown that, after initial hs-cTnT testing on
 presentation, there are a significant proportion of patients (54%) who would require further
 troponin testing after 1 hour as they were stratified in the observational zone on the
 initial troponin test. Despite the mandated repeated troponin at 1 hour, Marjot et al also
 showed that in real world practice, the mean time to repeat troponin was still 2.9 hours and
 that after training and implementation of the algorithm for 3 months, over 65% of patients
 still had their troponin taken at least 90 minutes after the first [4]. Similarly, in a
 sub-study of the ROMICAT II trial, Ferencik et al also found that a substantial 86.9% of
 patients had intermediate hs-cTn levels on initial testing and the addition of a second or
 third hs-cTn level did not improve risk stratification [5]. A study involving hs-cTnI (in a 2
 hour algorithm) by Lindahl et al showed that, 47.1% remained in the observational zone on
 initial troponin. After a repeat troponin 2 hours later, 25.5% of patients, remained in the
 observational zone [6]. This presents an opportunity for a possible alternative means of
 further evaluating the initial observational zone cohort of patients in a more efficient
 manner.

 Furthermore, multiple studies also showed that, even after repeat serial 1-hour troponin, a
 significant proportion of patients remains in the intermediate "observational zone" category
 and this is associated with mortality and adverse cardiac event risks. Suggestions for
 further management of these patients is not standardised and is guided by possible further
 repeat troponin and/or invasive or non-invasive cardiac imaging [2]. In a prospective
 international multicentre trial, Mueller et al found that 22.5% of patients remained in the
 observational zone and cumulative mortality for this cohort was 0.7% at 30 days but increased
 substantially to 9.6% at 365 days [7]. Similarly, Reichlin et al found that 24.1% of patients
 were found to be in the observational zone. In this cohort, the prevalence of acute MI was
 18.6% and the cumulative mortality was 1.6% at 30 days, rising to to 16.5% at 2 years
 follow-up [8]. Mokhtari et al evaluated major adverse cardiac events (MACE) at 30 days in an
 observational study where the 1-hour hs-cTnT algorithm supplemented by patient history and
 ECG ("extended algorithm") was compared with an algorithm using hs-cTnT alone (troponin
 algorithm). Despite the addition of patient history and ECG, the proportion of patients
 remaining in the observation zone was not significantly different between the two algorithms
 and was found to be of the order of 25-27%. In the extended algorithm the 30 day MACE event
 rate including unstable angina was 10.1% in the observational zone cohort [9]. A study by
 Jaeger et al showed that 33% of patients still remained in the observational zone and that
 the cumulative mortality was found to be 0.6% at 30 days and 3.55 at 360 days [10]. These
 studies aptly demonstrate the presence of a significant cohort of patients who remain in the
 observational zone despite second troponin testing. Thus, again there is a pressing need to
 clarify risk stratification and further clinical management to reduce the proportion of
 patients in the observational zone.

 1.2 Possible role for computed tomography coronary angiography The use of computed tomography
 coronary angiography (CTCA) in patients with acute chest pain has been shown to be safe [11],
 with high sensitivity and negative predictive value for coronary artery disease [12-15] and
 cost-effective with decreased time to diagnosis and earlier discharge from the ED [11, 16].
 The finding of coronary artery disease on CTCA has been shown to predict prognosis, with
 significantly worse MACE for patients with >50% stenoses, compared to those with <50%
 [17-19]. Historically 10% of patients with clinical Non-ST-elevation myocardial infarction
 (NSTEMI) on conventional troponin analysis were found to have unobstructed (<50% stenosis)
 coronary arteries on invasive coronary angiography. Subsequently it has been shown that
 approximately 10% of these have actual evidence of subendocardial infarction when
 investigated on late-gadolinium enhanced cardiac MRI (CMR) [20]. Therefore, in the era of
 high-sensitivity troponin assays, the percentage of patients with actual evidence of
 infarction would be even less in the ruled in group. Hence in our proposed research clinical
 pathway (detailed in section Experimental details and design of proposed investigation), the
 investigators have selected the conservative value of <25% stenosis to rule out AMI.

 Very few studies have examined the possible role of CTCA in the era of hs-cTn's. A sub-study
 of the ROMICAT II trial by Ferencik et al, showed that CTCA, with advanced plaque assessment
 and hs-cTn, significantly decreased the proportion of patients who had been classified in the
 intermediate category on initial hs-cTn from 43.8% to 24.4% when compared with conventional
 slow release troponin and traditional CTCA assessment (based on luminal stenosis alone).
 However, significant drawbacks of the study included the observational design and the
 unlimited time for CT interpretation. [5].

 The prospective randomised BEACON study compared the use of CTCA in addition to hs-cTn with a
 conventional management strategy involving hs-cTn alone. The authors concluded that the CTCA
 supplemented strategy did not meet the primary endpoint of identifying more patients with
 significant CAD requiring revascularisation. The use of CTCA also did not shorten hospital
 stay nor allow for more direct discharge from the ED, despite 42% of patients having no
 identifiable CAD and serial troponin testing being carried out at 3-6 hours. The main
 benefits of CTCA included significantly lower direct medical costs and less out-patient
 testing. However, duration of hospital stay was not the primary endpoint and the exclusion
 criteria did not include a specified lower limit for hs-cTn for ruling out AMI and only
 patients with no coronary disease were deemed to be suitable for A&E discharge [21]. Given
 the drawbacks of these studies, there is a compelling need to compare the performance of a
 management strategy involving hs-cTn supplemented by CTCA in a direct prospective randomised
 fashion, with usual standard of care involving serial hs-cTn alone, in the cohort of acute
 chest pain patients deemed to be in the intermediate observational zone according to the
 initial hs-cTn result.

 2. Study Objectives and Design 2.1 Aim of the study In patients with ACP requiring serial
 hs-cTn testing, to perform a head-to-head comparison of a management strategy involving
 serial hs-cTn supplemented by CTCA versus the conventional standard of care management guided
 by serial second hs-cTn alone in a randomised prospective trial. To the best of the author's
 knowledge this study will provide the first prospective and randomised data pertaining to
 hospital length of stay as a primary outcome in the use of CTCA on this ACP cohort (with an
 intermediate observational zone category) on initial hs-cTn results presenting to the ED in a
 tertiary hospital (see Study 1 below).

 It will also provide further data on the influence of traditional and more advanced CTCA
 diagnostics (e.g. traditional CT stenosis assessment, advanced plaque characterisation) in
 clinical decision making, incremental to that provided by hs-cTn based care alone in patients
 with acute chest pain (see Study 2 below).

 2.2 Original hypothesis The use of CTCA will lead to improvements in hospital length of stay
 and risk stratification and clinical management of patients in the intermediate/observational
 zone category on initial hs-cTn when compared with standard of care involving serial hs-cTn
 alone.

 2.3 Experimental Details and Design of the Proposed Investigation

 The proposed work is divided into two clinical studies:

 Study 1: Prospective, randomised single-centre trial to compare hospital length of stay,
 patient clinical management and outcomes between standard of care supplemented by CTCA versus
 standard of care alone, in ACP patients found to be in the intermediate observational zone
 category on initial hs-cTn in an acute hospital setting.

 The times for recruitment will be from 8am to 4pm, Mondays to Fridays (inclusive). If
 recruited, the patients will be randomised to either (Arm A): undergo early CTCA along with a
 serial second hs-cTnT; or (Arm B): undergo standard of care involving serial hs-cTnT alone.
 Patients in both arms will be consented to have CTCA. However, Arm B (standard of care arm)
 will be blinded from CTCA findings and will have standard of care based clinical management
 according to serial hs-cTn. The CTCA data in Arm B will be used for Study 2 (see below).

 Arm A: CTCA assessment will be carried out in Arm A while the patient would normally be
 waiting to have their repeat serial hs-cTn taken or waiting for the blood test result.

 Patients with <25% stenosis on CTCA will have AMI ruled-out and may be considered for
 discharge or alternative reasons for their clinical presentation may be investigated. The
 results of these CTCA scans will be made available to the patients' clinical care team and
 further management decisions will be left to their discretion.

 Arm B: Patients in this arm will be managed according to standard of care, which includes
 serial hs-cTn testing. These patients will also have CTCA carried out, but the CTCA
 assessment will not form part of the patients' clinical management as clinicians will be
 blinded to CTCA findings. Furthermore, unlike Arm A, CTCA image interpretation will not take
 place in the acute hospital setting. It will be carried out in the following days. The whole
 CTCA procedure will be carried out after the patient has had their hs-cTn taken and while the
 patient is waiting for their hs-cTn result (as the investigators would not like the CTCA to
 delay the staff members from taking the blood test).

 Study 2: Sub-analysis of CTCA + biomarkers arm (Arm B): Analysis of the CTCA data-sets will
 be carried out including luminal stenosis, and plaque characterisation. Thereafter this
 information will be revealed to a select group of clinicians, who will be asked (in a virtual
 setting) to comment on possible changes to their original (hs-cTn based) clinical management
 plans in the light of the information gleaned from the existing CTCA datasets. From existing
 CTCA stenosis data, the cardiology clinicians will be asked to comment on any changes to
 their clinical management plan if they were given the following information:

 (i) hs-cTn + CTCA stenosis (ii) CTCA stenosis + CT plaque characterisation (iii) A
 combination of the above. The investigators will also make a comparison between these virtual
 plans of action and actual course of action among patients who undergo invasive coronary
 angiogram +/- invasive FFR assessment as part of their routine care.

 CT-Plaque Characterisation AMI results from sudden coronary luminal thrombosis, which can
 occur from any of three underlying pathological lesions: plaque rupture, plaque erosion and
 calcified nodules. Plaque rupture represents most of the underlying pathologies for AMI and
 the precursor coronary lesion is known as thin capped fibroatheroma (TCFA). These tend to be
 composed of a large lipid-rich necrotic core, thin and intact fibrous cap, spotty calcium,
 inflammation due to infiltration by macrophages and some smooth muscle cells [24].

 High risk morphological features of TCFA that can be identified on CTCA plaque assessment
 include: (a) napkin ring sign (b) positive remodelling (c) spotty calcification and (d) low
 attenuation.

 2.6 Study Statistics The investigators will first inspect the normality of the distribution
 of the outcome variable. If it appears as though the distribution is not normal as expected,
 then the investigators will use non-parametric tests (Mann-Whitney U test); differences
 between groups will be constructed using 10,000 bootstrap simulations on the difference in
 medians, and derive associated confidence intervals and p-values. If there are any
 significant imbalances in any covariate(s) between the two groups, then the investigators
 will also perform quantile (specifically median) regression analysis on the difference
 between median length of stay between the two groups, adjusted for these covariate(s). To
 estimate the standard errors for the difference in medians, 10,000 bootstrap simulations of
 this quantile regression will be performed. If there are any significant imbalances, then the
 adjusted analysis will be considered the main analysis, otherwise the univariate analysis
 will be taken to be the main analysis. If the data are Normally distributed then standard
 regression techniques will be used.

 2.7 Cost and Economic Analysis The cost and cost-effectiveness analyses will assess whether
 the addition of CTCA within the ED setting to the conventional clinical pathway without acute
 imaging will produce any changes in terms of total costs and/or cost-effectiveness analyses.
 For the purposes of the secondary objectives of cost analyses and economic evaluations
 (consistent with secondary outcomes) quality of life and symptoms will be measured using the
 EQ-5D-5L questionnaire at baseline after the ED episode and then monthly for the first three
 months and three monthly thereafter. All relevant costs from an NHS and Personal Services
 perspective will be considered using a top-down costing strategy (consistent with GSTFT
 finance data). Cost-effectiveness will be estimated in terms of the incremental cost per
 quality-adjusted life year (QALY) of comparing both clinical pathways (with and without the
 use of CTCA in acute setting). This ratio will be calculated using the area under the curve
 for health utility using the EQ-5D-5L and health service costs up to one year. Sensitivity
 analyses will explore the potential impact of major adverse events upon lifetime costs and
 QALYs as well as the adoption of a societal perspective. Existing published models will
 constitute the base for long-term modelling of both clinical pathways. Lifetime QALYs and
 costs of surviving patients will be estimated from published sources of life expectancy,
 annual costs and corresponding annual utilities. It is hypothesised that patients in whom
 coronary artery disease is identified, will adhere better to strategies that include primary
 and secondary prevention. This means that the early use of CTCA might hold benefits in the
 short-term) as well in the medium and long-term.

 2.8 Timeline In our internal audit, patients who presented with acute chest pain to the ED at
 GSTFT, and were found to be in an intermediate grey zone on initial troponin analysis and who
 required a second troponin amounted to 26 patients per week. As the investigators aim to
 recruit patients Monday to Friday from 8am to 4 pm, it is anticipated that it may be possible
 to recruit 5 patients per week in total. Given the target of 250 patients in the study,
 recruitment is likely to take approximately 52 weeks to achieve.

 Follow up Procedures Patients will be followed up at 1, 2, 3, 6, 9 and 12 months following
 the hospital visit, to capture all relevant costs and outcomes.

 It is estimated that 30% of participants enrolled in the study may be lost to follow-up.

 Data collection General and study specific data Data will be collected by the research team
 from routinely collected NHS records and will include several categories, such as: baseline
 demographics, co-morbidities, ECG results, admission and discharge diagnoses, cardiology and
 other relevant investigations or interventions, repeat hospitalisations and adverse events.

 Patient questionnaires Patients will receive a call (at 1, 2, 3, 6, 9 and 12 months) to
 collect key information around resource use, patient quality of life and patient
 satisfaction. During this contact, participants will be asked: i) about the presence and
 degree of pain/discomfort, their level of concern and patient satisfaction using a scale of
 0-10; ii) EQ-5D-5L questionnaire, with five questions; iii) NHS resource use, due to the
 participant's ACP episode; and iv) the presence of any Major Adverse Cardiac Events (MACE).
 This information above will be required to achieve secondary objectives of the study.

 3. CTCA Procedures and findings 3.1 CTCA Procedure The CTCA exam will be performed on a new
 generation a multi-detector dual-source CT scanner.

 The investigators will try to ensure optimum CTCA images by attempting to minimise coronary
 and chest wall motion artefact through reducing heart rate to below 63 beats per minute (bpm)
 and by getting the patients to hold their breath for 10 - 12 seconds. If the heart rate is
 above 63 bpm and the systolic blood pressure (BP) is above 100 mmHg, intravenous
 beta-blockers) will be given to achieve the target heart rate. To further optimise coronary
 images, sublingual glyceryl trinitrate (GTN) will be given if the systolic BP is above 90
 mmHg. Pre-CTCA renal function will be available from routine bloods samples that are taken as
 part of standard of care work-up of patients presenting to the ED with acute chest pain.
 Female patients of potential child bearing age will be screened for the possibility of
 pregnancy according to the local Guy's and St. Thomas' Radiology protocols.

 3.2 CTCA Image Interpretation and Reporting

 The CTCA will be interpreted and reported by an experienced Radiologist or Cardiologist with
 a minimum of Level II certification in cardiac CT angiography. Angiograms will be reported
 using the standard 15 segment model [22]. A stenosis will be graded in severity according to
 the following classification [23]:

 1. Minimal: 0-24%

 2. Mild: 25-49%

 3. Moderate: 50-70%

 4. Severe: >70%

 5. Total Occlusion: 100% As discussed previously, patients with <25% stenosis will have AMI
 ruled-out.

 3.3 CTCA Results For Arm A, CTCA image interpretation and reporting will be carried out
 as early as possible in the acute hospital setting, while the patient is an in-patient.
 The results will be made available to the patients' clinical care team and further
 management decisions will be left to their discretion.

 Patients in Arm B will also have CTCA carried out but the CTCA assessment will not form
 part of the patients' clinical management as this arm will be blinded to CTCA findings.
 Furthermore, unlike Arm A, CTCA interpretation followed by reporting will not take place
 in the acute hospital setting. Should the CTCA be found to have significant high risk
 CAD e.g. >50% stenosis in the left main (LM) coronary artery, and/or >50% stenosis in
 the proximal left anterior descending (LAD) coronary artery, they will be un-blinded and
 kept in a separate registry. Their results will be discussed with the hospital care team
 and if required, an urgent cardiology out-patient referral will be made to enable
 further clinical management.

 3.4 CTCA Incidental Findings Pooled studies show: (i) an incidental extra-cardiac
 finding in 44% of patients undergoing CTCA; and (ii) the diagnosis of a major finding in
 16% of the CTCA exams [25]. Incidental findings on CTCA will be documented in the CTCA
 report. In the case of Arm A (Study 1), the clinical care team will be made aware of the
 finding through the report. In Arm B any clinically significant findings e.g. cancers
 and/or prognostically significant coronary artery disease will be notified as a
 Radiology alert to the clinical care team and the patient's general practitioner.

 4. Sample Size, Selection and Withdrawal of Subjects 4.1 Sample Size Waiting times often
 exhibit a skewed distribution, and so the sample size calculation was based on the
 difference in median waiting time.

 To estimate the sample size needed to observe a one-hour reduction in median hospital
 length of stay, normal techniques based on standard deviation estimates are not valid.
 The investigators therefore used a random sample of 49 patients undergoing the current
 pathway as the control 'population', and created an equivalent treatment 'population' by
 multiplying the waiting times of the 49 sampled patients by a constant such that the
 median was reduced by one hour; this constant was found to be 0.799.

 For a given sample size n, 10,000 Monte Carlo simulations were performed by sampling n
 patients with replacement from each of the two groups, and the p-value from a
 Mann-Whitney U test was calculated for each simulation. The proportion of these 10,000
 simulations with a p-value below 0.05 was recorded as the power for that sample size n.
 The sample size was varied until a power of 0.8 was obtained, and was found to be 250
 patients in total (125 patients in each arm of the study).

 Patient drop-out is anticipated to be minimal as all patients, by definition of the
 primary outcome, will be in hospital for the length of their hospital stay, and
 therefore their length of stay will be recorded.

 5. Study Procedures 5.1 Screening Procedures Patients with suspected ACS eligible for
 the study will enter GSTFT via the ED at St Thomas' Hospital. If the initial ECG shows
 no ischaemic changes and the initial hs-cTn result cannot rule in or rule out AMI, the
 patient will be identified as a potential recruit to the study by the clinical care
 team.

 A screening log will be maintained by the site and kept in the Investigator Site File.
 This will record all potentially eligible patients approached about the study and the
 reasons why they were not registered in the study if this is the case.

 5.2 Consenting Participants Once a potential participant is identified by the clinical
 team, and if the patient meets the inclusion criteria (and none of the exclusion
 criteria), a trained member of research team will obtain signed informed consent from
 the patient.

 This procedure will be supported by a patient information sheet that appropriately
 explains the aims, methods, anticipated benefits and potential hazards of the study.

 It is anticipated that the consent process will take no longer than 15 minutes. It will
 be explained to the patient that it is his/her right to ask to be withdrawn from the
 study at any point in time.

 Written informed consent on the current approved version of the consent form for the
 study will be obtained before any study-specific procedures are conducted, and a copy
 will be given to the patient and kept in the patient's medical notes. The discussion and
 consent process will be documented in the patient notes.

 The patient's capacity will be assessed by trained and delegated clinical/research staff
 who have completed study specific training and have been delegated this responsibility
 by the Principal Investigator (PI).

 Research staff are responsible for:

 -  Assessing the patient's capacity to provide informed consent.

 -  Checking that the current approved version of the information sheet and consent
 form are used.

 -  Checking that information on the consent form is complete and legible and the
 patient has completed/initialled all relevant sections and signed and dated the
 form.

 -  Checking that an appropriate member of staff has countersigned and dated the
 consent form to confirm that they provided information to the patient.

 -  Checking that an appropriate member of staff has made dated entries in the
 patient's medical notes relating to the informed consent process (i.e. information
 given, consent signed etc.).

 -  Following registration:

 -  Adding the patient study number to all copies of the consent form, which
 should be filed in the patient's medical notes and investigator site file.

 -  Giving the patient a copy of their signed consent form and patient information
 sheet.

 -  Respecting the right of the patient to refuse to participate in the study without
 giving reason as all patients are free to withdraw at any time.

 5.3 Randomisation Procedures Once patients consent to participate in the study, they
 will be randomised into the intervention group (i.e. with CTCA) or the control group
 (i.e. hs-cTn based standard of care) on a 1:1 ratio.

 Randomisation will be carried out via the use of opaque sealed envelope block
 randomisation method. Both the block randomisation list and the sealed envelopes will be
 produced by the statistician. Each block will contain 5 envelopes, which would translate
 to 50 blocks. 25 blocks will contain 3 envelopes for Arm A and 2 envelopes for Arm B.
 The remaining 25 blocks will contain 3 envelopes for Arm B and 2 envelopes for Arm A.
 Each block will also be randomly arranged. The sealed opaque envelopes/blocks used to
 assign patients to either arm will be prepared by an individual external to the study.
 The recruiter will not be able to identify which arm a potential participant is going to
 be randomised to until after he/she has received informed signed consent from the
 potential participant.

 Once randomised onto the study, the patient will be given a study number. This will be
 documented in the enrolment log.

 5.4 Radiation assessment The proposed study includes only one scan per patient covering
 approximately the cardiac anatomy from the aortic root/pulmonary arteries level down to
 below the inferior border of the heart. The CT scan protocol will use standard
 prospective ECG gating. If necessary intravenous beta-blockers will be given to achieve
 the target heart rate (below 63 beats per minute). If for clinical reasons (e.g.
 elevated heart rate despite the use of oral and/or intravenous beta-blockers) it is not
 possible to use the prospective CTCA scanning protocol, the patient will not undergo the
 CTCA examination and therefore will not take part in the study. The typical Dose-Length
 Product (DLP) for the prospective CTCA scan is expected to be in the region of 350
 mGy.cm. This leads to an estimate cardiac CT dose of approximately 9mSv per scan. To
 provide an upper estimate of dose that is not expected to be exceeded, the 95th
 percentile plus 20% is taken. This gives a DLP of 640mGycm which corresponds to an
 effective dose of 16mSv. These effective doses estimates are based on a previous dose
 (DLP) audit of 30 CTCA scans performed on adult patients between 02/03/2017 and
 20/03/2017 on the Siemens Force scanner at St Thomas' Hospital using the 'CaScore Turbo
 Flash' or the 'Coronaries Prospective' protocol. The total research protocol dose (TRPD)
 for this study is set at 16mSv all of which is due to the CTCA imaging research
 procedure, i.e. additional to standard care. It is noted that some patients involved in
 this study may go on to have other procedures involving radiation as part of their
 standard care. These are difficult to fully characterise and are not included in this
 dose calculation. The total risk expressed as the total detriment (cancer incidence
 weighted for lethality and life impairment and the probability over two succeeding
 generations of severe hereditary disease) is estimated at approximately 1 in 1100 for
 the full TRPD dose. The TRPD value corresponds to approximately 7 years of natural
 background radiation exposure, where the average natural background radiation per capita
 is 2.2 mSv in the UK.

 6. Assessment of Safety

 A serious adverse event is any untoward medical occurrence that:

 -  Results in death;

 -  Is life-threatening;

 -  Requires in-patient hospitalisation or prolongation of existing hospitalisation;

 -  Results in persistent or significant disability/incapacity; or

 -  Other important medical events. 6.1 Ethics reporting A serious adverse event (SAE)
 occurring to participant would be reported to the REC that gave a favourable
 opinion of the study where in the opinion of the Chief Investigator the event was:
 'related' - that is, it resulted from administration of any of the research
 procedures; and 'unexpected' - that is, the type of event is not listed in the
 protocol as an expected occurrence. Reports of related and unexpected SAEs would be
 submitted within 15 days of the Chief Investigator becoming aware of the event,
 using the NRES report of serious adverse event form.

 All related AEs that result in a patient's withdrawal from the study or are present at
 the end of the study, should be followed up until a satisfactory resolution occurs. A
 patient may also voluntarily withdraw from treatment due to what he, or she, perceives
 as an intolerable AE. If either of these occurs, the patient would undergo an end of
 study assessment and be given appropriate care under medical supervision until symptoms
 cease or the condition becomes stable.

 7. Study Steering Committee The Study Steering Group will meet at fixed points during
 the study and will include patient representatives.

 Data Monitoring and Ethics Committee (DMEC) functions will be embedded in the Study
 Steering Committee. The Study Steering Committee will have access to unblinded
 comparative data. The committee will monitor data collection methods and make
 recommendations regarding whether there are any ethical or safety reasons why the study
 should not continue.
Inclusion Criteria:

 1. Patients above 18 years of age with ischaemic sounding chest pain prompting visit to
 the emergency department (suspected ACS).

 2. No-ischaemic ECG changes (i.e. no ST-segment elevation or depression 1mm in 2 or more
 contiguous leads, and/or T-wave inversions).

 3. Episode of chest pain within last 12 hours.

 4. Initial troponin in the intermediate range (5-50ng/L).

 Exclusion Criteria:

 1. STEMI.

 2. Signs and symptoms of acute heart failure and/or haemodynamic instability.

 3. Dynamic ischaemic ECG changes.

 4. Patient not suitable to undergo CTCA

 1. Inability to breath hold for 10 seconds

 2. Severe renal impairment (eGFR <30 mL/min)

 3. Contraindication to beta-blockers (not relevant for patients with baseline sinus
 rhythm at rate of <63bpm)

 5. Atrial Fibrillation on ECG.

 6. Patients with known significant obstructive coronary artery disease (>50% stenosis) on
 previous invasive or CT coronary angiogram.

 7. Patients with previous PCI/CABG revascularisation.

 8. Patients with a history of congenital heart disease.

 9. Patients with known coronary artery anomalies.

 10. Patients who lack capacity to give consent or participate in the study.

 11. Previous recruitment to the present study.

 12. Known pregnancy or patients who are currently breast feeding.

 13. Prisoners.

 14. Patients involved in current or a recent (within the last 4 months) CTIMP trial.