Performance of the coronary calcium score in an outpatient chest pain clinic and strategies for risk stratification

Abstract Background Coronary artery calcium score (CAC) is an objective marker of atherosclerosis. The primary aim is to assess CAC as a risk classifier in stable coronary artery disease (CAD). Hypothesis CAC improves CAD risk prediction, compared to conventional risk scoring, even in the absence of cardiovascular risk factor inputs. Methods Outpatients presenting to a cardiology clinic (n = 3518) were divided into two cohorts: derivation (n = 2344 patients) and validation (n = 1174 patients). Adding logarithmic transformation of CAC, we built two logistic regression models: Model 1 with chest pain history and risk factors and Model 2 including chest pain history only without risk factors simulating patients with undiagnosed comorbidities. The CAD I Consortium Score (CCS) was the conventional reference risk score used. The primary outcome was the presence of coronary artery disease defined as any epicardial artery stenosis≥50% on CT coronary angiogram. Results Area under curve (AUC) of CCS in our validation cohort was 0.80. The AUC of Models 1 and 2 were significantly improved at 0.88 (95%CI 0.86–0.91) and 0.87 (95%CI 0.84–0.90), respectively. Integrated discriminant improvement was >15% for both models. At a pre‐specified cut‐off of ≤10% for excluding coronary artery disease, the sensitivity and specificity were 89.3% and 74.7% for Model 1, and 88.1% and 71.8% for Model 2. Conclusion CAC helps improve risk classification in patients with chest pain, even in the absence of prior risk factor screening.


| INTRODUCTION
Chest pain is one of the top referral reasons to cardiology outpatient clinics. The prevalence of coronary artery disease at outpatient chest pain clinics varies around 10-20%. [1][2][3] While majority of patients are told to be free of obstructive coronary artery disease (CAD) after examination and testing, this clinical encounter is a good opportunity to provide advice and initiate therapy for primary prevention.
The coronary artery calcium (CAC) test has rapid turnaround and requires little preparation. This provides the option of same-day testing at an outpatient clinic. Depending on chest pain history, low risk patients with low CAC may be discharged on the same day with chest pain advice, saving future visits for cardiac tests and follow up. A zero calcium score is strong negative risk predictor for coronary artery disease, with a negative predictive value of 99%, sensitivity of 91%, and specificity of 64%. 4 Moreover, conventional risk scores, such as the CAD Consortium The CAC also guides prescription of statin therapy, 5,6 which is important in the primary prevention of myocardial infarction. While functional tests such as myocardial perfusion imaging and stress echocardiogram give information on the area and extent of ischemia due to a coronary artery lesion, the CAC gives physicians actionable information to modify risk through optimal medical therapy. Statins are favored in non-zero calcium scores, especially in those aged 55 and above. 7 The primary aim of this study was to determine the performance CAC as a risk classifier when added to conventional risk factor variables and chest pain history, by creating a risk model that can be applied to daily clinical use. One common challenge in clinic is lack of prior health screening, leading to underreporting of pre-existing cardiovascular risk factors. Hence, we also looked at the performance of the CAC in the absence of cardiovascular risk factor variables.

| METHODS
This was a cross sectional study. Recruitment occurred between January 01, 2014 and December 31, 2017. Recruitment occurred at the National Heart Centre Singapore cardiology outpatient clinics.
Consecutive patients with chest pain referred to the CT laboratory for testing during that period were recruited. The National Heart Centre Singapore is a 185-bed national and regional referral centre for cardiovascular medicine.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration. Informed consent was obtained from all patients for being included in the study.
The total sample size was 3518 patients. All patients underwent computed tomography coronary angiogram (CTCA) with readouts of degree of coronary artery stenosis and CAC.
The primary outcome of interest was the presence of obstructive coronary artery disease, defined as any epicardial artery stenosis of ≥50% on CT coronary angiogram. Epicardial artery stenosis of ≥50% was the same outcome used by the CAD Consortium score, our reference risk score. 8 All patients presenting to the CT laboratory had their baseline demographics, chest pain history and self-reported cardiovascular risk factors collected by a nurse clinician. The CAD I consortium score 9 was the conventional risk calculator used for comparison.
The CTCA and CAC were performed using a Toshiba Aquilion ONE scanner with 160 mm coverage and 320 slice detector. Calcium scan was prospectively gated and scanned over a single heartbeat with a gantry rotation and X-ray exposure time of 0.35 s, 0.5 mm slice collimation, tube voltage of 120 kV, and tube current of 140 mA.
Images were reconstructed at 3.0 mm slice thickness for calcium score. Assessment was carried out using the Vitrea Calcium software and Agatston scoring schema. All studies were assessed for arterial lumen stenosis for all coronary arterial segments. Images were assessed using volume-rendered images, curved multiplanar reformations, and cross-sectional images in available phases as well as from sharp and standard kernels. Visual assessment of arterial segment lumen diameter stenosis was carried out. In assessing stenosis, the minimum lumen diameter was identified for each arterial segment and then compared with a reference site of a disease-free site in closest proximity to the lesion site.
The outcome of significant coronary artery stenosis on CTCA was determined by two independent radiologists who were not involved in the baseline data collection. Disagreements between the two readers was resolved by consensus.
The study complied with the Declaration of Helsinki and was approved by our Centre's Institutional Review Board.

| Statistical methods
Continuous normally distributed variables were compared by t-test and categorical variables by chi square test in univariate analysis. Normally distributed variables were presented as mean and standard deviation, while non-normal variables were presented as median and its interquartile range.
The cohort was divided into derivation and validation cohorts, in two thirds (2344 patients) and one third (1174 patients), respectively.
We built two logistic regression models including calcium score to predict the probability of having obstructive coronary artery disease:  These models were then compared to the previously published CAD I consortium 9 score (CCS) which uses cardiovascular risk factors and the Diamond-Forrester chest pain history for risk prediction. We calibrated the CCS using our derivation cohort.
Discriminative abilities of the different models were evaluated by the area under to receiver operating curve, net reclassification index (NRI) and integrated discrimination improvement (IDI) 11

| RESULTS
The baseline demographics of the cohort (presented separately as the derivation and validation groups) are presented in ter than Model 2 p-value = .009 (see Figure 1). All models were of good fit, by non-significant Hosmer-Lemeshow tests. Represents groups of patients who were appropriately uptriaged or downtriaged by addition of calcium score.
CT calcium score. This can impact workflow and reduce follow-up clinic visits.
Additionally, a zero calcium score confers good prognosis in the setting of chest pain with 1% annual event rate, 12 despite the risk of having non-calcified plaques. 15 The annual event rate of a zero calcium score is lower than a negative stress test (2.1%), based on the PROMISE study; majority of cardiac events occurred in patients with non-zero calcium scores. 12 This shows the additional prognostic value of zero calcium score. A non-zero calcium score hence provides opportunity for initiation of statins, especially in those aged 55 and above or with an increased Atherosclerotic Cardiovascular Disease (ASCVD) score, as recommended by the 2018 ACC/AHA Cholesterol Guidelines. 7 Apart from diagnosing obstructive coronary artery disease, primary prevention advice is essential for cardiovascular disease management. For every 1 mmol/dl LDL-C reduction with statin therapy, the relative risk of major adverse cardiovascular events is reduced by approximately 20-25%, and all-cause mortality is reduced by 10%. 16 The CAC provides actionable information that may not be available from a negative stress imaging test. The rates of significant plaque in the setting of zero calcium in our study is 1.9%, which is largely similar to findings from other chest pain studies. 12,17,18 Conversely, patients with risk scores 30% and above for CCS, Model 1 and 2, or CAC > 400 have very high likelihood of coronary artery disease (see Table 4). At the cut-off of >0.30, the specificities products. 22 It also does not require additional heart rate lowering agents 23 or blood tests to ensure adequate renal function. The radiation dose of the CT calcium score in our laboratory is low at 0.5 mSV compared to a full CT coronary angiogram (2.7 mSV) 24 and myocardial perfusion imaging test (5.3 mSV). 25 There are limitations to our study. The study population was intermediate risk, with average CAD consortium score of 15%. These patients were referred from the primary care setting to the cardiology specialist clinic for investigation of chest pain. The risk profile of the study population was lower compared to previous cardiac CT-based studies, 17,19,26 hence further calibration may be required before the model can be used on higher risk populations. The study cohort was a multi-ethnic Southeast Asian population; the lower cardiovascular risk profile of Asians (apart from South Asians) when compared to Western populations may contribute to the lower risk profiles seen in our study. The reference primary outcome was CT coronary angiogram detected stenosis, instead of gold standard invasive coronary angiography. Long term follow-up for major adverse cardiovascular outcomes was also not available.
Our study adds to literature by addressing the common challenge of unknown cardiovascular risk factors at the first clinic visit.
As CAC is reflective of the arterial age 27 under the influence of cardiovascular comorbidities such as diabetes mellitus, the study showed that the CAC is a good risk classifier, even in the absence of such information. Without knowledge of cardiovascular risk factors, the ROC performance of Model 2 remains good at 0.87 in the validation cohort.
We also supported findings from prior studies; prior studies 15,28 previously discussed the value of a zero calcium score in chest pain clinics and previous work from Genders et al 9

| CONCLUSION
The coronary CAC is a useful aid to streamline workflow in chest pain clinics at an outpatient setting.