Utility of CT coronary angiography in non-ST elevation acute coronary syndrome

Introduction

Coronary computed tomographic angiography (CCTA) has evolved as a logistically simple, accurate, and low-risk non-invasive test which allows visualisation of the coronary arteries¹, and has a negative predictive value approaching 100% for excluding the presence of coronary artery disease (CAD)². The European Society of Cardiology (ESC) guidelines for chronic coronary syndrome recommend CCTA as the initial diagnostic test to diagnose CAD in symptomatic patients with a low-to-intermediate pre-test likelihood of coronary artery disease¹. More recently, the updated ESC guidelines for the management of patients with acute coronary syndrome (ACS) without persistent ST-segment elevation recommend CCTA as an alternative diagnostic strategy to invasive angiography to exclude ACS when there is a low-to-intermediate likelihood of coronary artery disease in combination with normal or inconclusive cardiac biomarkers and/or electrocardiogram (ECG)³.

A metanalysis of four randomised controlled trials (RCTs) which included 3,266 patients and compared CCTA with the standard care triage of acute chest pain in the emergency department (ED) showed comparable outcomes between the two approaches⁴. The rate of death, myocardial infarction and return emergency department visit was similar between the two groups. However, the pooled odds ratio for recurrent hospitalisation with acute coronary syndrome was 1.20 (95% CI: 0.67 to 2.2, p= 0.54) suggesting that there may be potential harm with only using CT to exclude ACS. The emergency department costs and average length of stay were lower in patients undergoing CCTA. The use of CCTA in the emergency department also resulted in a modestly increased downstream incidence of invasive coronary angiography and revascularisation (percutaneous coronary intervention/coronary artery bypass grafting) by 2% compared with the usual care group. There was 1 additional invasive angiogram for every 48 patients and 1 additional revascularization for every 50 patients evaluated with CCTA. It is important to note that the majority of patients included in the metanalysis had normal cardiac biomarkers with normal or inconclusive findings on ECG and the overall prevalence of ACS was low across all studies. Additionally, none of these studies used high sensitivity cardiac troponin (hs-cTn) assays, which are known to substantially reduce the delay to diagnosis, translating into early discharge from emergency department^5,6.

Subsequently, a randomised controlled trial in patients presenting with symptoms suggestive of acute coronary syndrome to the emergency department and comparing a diagnostic strategy supplemented by early CCTA versus standard optimal care encompassing high sensitivity cardiac troponin assays, found no significant difference in the length of hospital stay or number of patients requiring invasive coronary angiograms and coronary revascularisations at 30 days⁷. However, when CCTA was used at an early stage in the work up of suspected acute coronary syndrome, it was found to be safe and associated with fewer outpatient investigations and overall lower treatment costs.

High sensitivity cardiac troponin assays have significantly improved our ability to confidently  ‘rule-out’ acute myocardial infarction in patients presenting to the emergency department with acute chest pain and inconclusive ECG⁸.  However, elevated high sensitivity cardiac troponin is not specific for atherosclerotic plaque rupture and a multitude of causes exist that may account for the mechanism of myocardial injury including arrhythmic, microvascular, non-coronary myocardial or non-cardiac systemic illnesses. Patients presenting with chest pain, inconclusive ECG and elevated troponin levels are typically treated as having non-ST segment elevation acute coronary syndrome (NSTEACS) and referred for an invasive coronary angiogram in accordance with current guidelines^3,9. Whilst CCTA improves the selection of patients benefiting from invasive coronary angiography in the setting of chronic coronary syndrome and troponin-negative ACS, it remains unclear whether patients with high sensitivity cardiac troponin levels above the 99th percentile would benefit from a non-invasive imaging strategy to identify those most appropriate for coronary revascularisation. First line use of CCTA in this setting as a ‘gatekeeper’ to the catheter laboratory would identify those with coronary artery disease and reduce the frequency of non-obstructive and normal coronary arteries at the time of invasive angiography.

The aim of this review is to provide a condensed summary of the studies investigating the strategy of performing early CCTA in patients with elevated high sensitivity cardiac troponin levels and a working diagnosis of NSTEACS.

The CARMENTA (The role of initial CARdiovascular Magnetic rEsoNance imaging and computed Tomography Angiography in non-ST elevation myocardial infarction patients) trial was a 3-arm, prospective, open-label, single-centre, randomised controlled, comparative effectiveness trial comparing a diagnostic strategy incorporating cardiovascular magnetic resonance imaging (CMR) or CCTA first as a gatekeeper for invasive coronary angiography with a control strategy (i.e. routine clinical care) in patients with NSTEACS¹⁰. There were 207 patients included in the study, of whom 69 were randomised to routine clinical care, 68 to the CMR-first diagnostic strategy, and 70 to the CCTA-first diagnostic strategy. 62% of the trial participants were male with a mean age of 64 + 12 years. The median peak high sensitivity cardiac troponin rise was 78 ng/l (interquartile range (IQR) 37-285 ng/L) indicating a low burden of myocardial injury in the study population. Importantly, 86% of the study participants had a GRACE risk score <140 which designated most of the patients recruited in the study as having a low-to-intermediate cardiovascular risk and thereby justifying an initial non-invasive strategy.

Outcomes

The study showed that compared with routine clinical care, implementing CMR or CCTA as a first line test reduced the proportion of patients referred for invasive coronary angiography during initial hospitalisation and at 12 months follow-up. There was no significant difference in length of hospital stay or major adverse cardiovascular outcomes (composite of all-cause mortality, recurrent MI, unplanned coronary revascularisation after the index event, or congestive heart failure requiring hospitalisation) at 1- and 12-month follow up. Similarly, median time to revascularisation during the index admission was similar amongst all groups.

The effective radiation dose was significantly higher in the CCTA-first group (13.0 mSv [IQR: 7.7 to 20.7 mSv]) compared with routine clinical care (4.1 mSv [IQR: 2.5 to 8.9 mSv]) and CMR-first strategies (4.9 mSv [IQR: 1.9 to 9.6 mSv]). Of all patients randomised to the CMR- and CCTA-first strategy and who underwent invasive coronary angiogram during initial admission, obstructive coronary artery disease was found in 69% (p=0.308) and 85% of patients (p=0.06), respectively as opposed to 61% of patients who were allocated to routine clinical care.

Limitations

This is single centre study with a small sample size and relatively low proportion of patients with a high GRACE risk score. Additionally, patients with a history of myocardial disease and/or other severe non-cardiac comorbidities were excluded, which limits the widespread applicability of the study. Although both CCTA- and CMR-first strategies showed a trend towards a reduced rate of invasive coronary angiography, this reduction came at the expense of increased radiation dose with the CCTA-first strategy and no significant difference in clinical outcomes at 1 month and 1 year when compared to routine clinical care. However, this was based on early duration follow-up and possibly unlikely to demonstrate any early clinical impact due to low event rates in the context of micro-infarctions. The study also did not report on the cost effectiveness of employing an upfront non-invasive strategy in this cohort of patients.

The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients with Acute Coronary Syndromes) trial evaluated the outcome of patients with confirmed non-ST elevation acute coronary syndrome randomised 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography¹¹. As an observational component of the trial, a clinically blinded CCTA was conducted prior to invasive coronary angiography in both groups to assess the diagnostic performance of CCTA using invasive coronary angiography as the reference standard¹². Of the 2147 patients recruited in the trial, CCTA was performed in 1023 (56%) patients.  More patients underwent CCTA in the very early group compared with the standard of care group (583 vs. 440; p < 0.001). The trial participants had at least one of the high-risk criteria with ST/T wave changes indicative of ischemia on ECG or an increase in biomarkers of ischemia (high sensitivity cardiac troponin). More than 40% of patients in both study arms had a GRACE risk score >140.

Outcomes

Most studies using CCTA compared with invasive angiography have been performed in the setting of ‘stable’ coronary artery disease without the presence of vulnerable plaque or luminal thrombosis. This study demonstrated that CCTA can be performed safely in patients with non-ST elevation acute coronary syndrome without major side effects or harm from delaying invasive coronary angiography. The diagnostic performance of CCTA to ‘rule out’ or ‘rule in’ significant CAD (>50% coronary artery stenosis) in patients with NSTEACS was high, with a negative predictive value (NPV) of 90.9%, sensitivity of 96.5%, a positive predictive value
(PPV) of 87.9% and a specificity of 72.4%. The overall accuracy of CCTA was 88.7%. The diagnostic performance of CCTA showed similar results for both treatment groups. The majority of patients with false negative CCTA results had coronary artery disease located in small side branches. Among patients who had undergone previous PCI the NPV and sensitivity were high
(91.7% and 99.1%), but the PPV and specificity were reduced to 84.7% and 36.7% respectively. The NPV for patients with GRACE risk score >140 was >95%. The PPV was comparable in all sub-groups, except in females who had a significantly lower PPV compared with men (p < 0.001). The specificity of CCTA was significantly lower among patients with previous myocardial infarction, previous PCI, and elevated troponin (p < 0.001).

Limitations

This is primarily a diagnostic accuracy study and no firm conclusion can be drawn in terms of clinical outcomes, thereby limiting the clinical applicability of the findings. This was an observational sub-study of the trial and there was a sizeable proportion of trial participants (44%) who did not undergo CCTA because the patients were either randomised outside of day time working hours or cancelled by the treating physician thus introducing a degree of selection bias. Although the study demonstrated high sensitivity and negative predictive values for ‘ruling out’ significant coronary artery disease in patients with NSTEACS, the diagnostic performance was inferior when compared to high sensitivity cardiac troponin assays (>99% sensitivity) in terms of ‘ruling out’ acute coronary syndrome.

The effective radiation dose was significantly higher in the CCTA-first group (13.0 mSv [IQR: 7.7 to 20.7 mSv]) compared with routine clinical care (4.1 mSv [IQR: 2.5 to 8.9 mSv]) and CMR-first strategies (4.9 mSv [IQR: 1.9 to 9.6 mSv]). Of all patients randomised to the CMR- and CCTA-first strategy and who underwent invasive coronary angiogram during initial admission, obstructive coronary artery disease was found in 69% (p=0.308) and 85% of patients (p=0.06), respectively as opposed to 61% of patients who were allocated to routine clinical care.

Limitations

This is single centre study with a small sample size and relatively low proportion of patients with a high GRACE risk score. Additionally, patients with a history of myocardial disease and/or other severe non-cardiac comorbidities were excluded, which limits the widespread applicability of the study. Although both CCTA- and CMR-first strategies showed a trend towards a reduced rate of invasive coronary angiography, this reduction came at the expense of increased radiation dose with the CCTA-first strategy and no significant difference in clinical outcomes at 1 month and 1 year when compared to routine clinical care. However, this was based on early duration follow-up and possibly unlikely to demonstrate any early clinical impact due to low event rates in the context of micro-infarctions. The study also did not report on the cost effectiveness of employing an upfront non-invasive strategy in this cohort of patients.

The recently presented RAPID CTCA trial was designed to evaluate patients presenting to the hospital with suspected or provisional acute coronary syndrome who were randomised 1:1 to cardiac CT angiography (n = 877) versus usual care (n = 871)¹³. The inclusion criteria included at least one of the following:

• Prior history of coronary heart disease
• Troponin >99th percentile
• Abnormal electrocardiogram

The mean age was 62 years with 36% of the trial participants female. Around 23% of the patients had a GRACE risk score >140 with 32% of the patients having a GRACE risk score of 109-140.

Outcomes

Although the study has not been published, the provisional data shows that a strategy of routine CCTA made little difference to treatment decisions or 1-year outcomes compared with standard care in intermediate-to-high-risk patients with chest pain and suspected acute coronary syndrome. The primary outcome of all-cause death and type 1 (spontaneous) or type 4b (stent thrombosis) myocardial infarction at 1 year occurred in 5.8% of the cardiac CT angiography group compared with 6.1% of the usual care group (p = 0.65). This finding was the same in all tested subgroups. Over half of the patients (52%) who underwent CCTA did not have any anatomical evidence of obstructive disease.  In the CCTA arm of the trial, fewer patients underwent invasive coronary angiography (hazard ratio of 0.81 [95% CI, 0.72 - 0.92, P = 0.001]), thus demonstrating the ‘gatekeeper’ role of CCTA in selecting patients for ICA. Despite a lower rate of invasive coronary angiography with CCTA, the invasive coronary angiography to revascularisation ratio was similar in both groups (hazard ratio of 1.03 [95% CI, 0.87 - 1.21]). In addition, routine CCTA strategy was associated with a similar length of hospitalisation (2.2 days vs 2.0 days) but modest reduction in health care costs ($9,494 vs $8,776).

Discussion

CCTA is a well-established diagnostic modality which reliably rules out obstructive coronary artery disease in patients with chronic coronary syndrome. In a prospective analysis of patients with symptoms of stable chest pain only 12% of patients having CCTA as a first line investigation underwent invasive coronary angiography¹⁴. In patients with NSTEACS, high-sensitivity cardiac troponin performs better as a ‘rule out’ test than CTCA partly because fewer patients re-present with acute coronary syndrome when using a biomarker- rather than imaging-guided strategy to initiate therapy. But should CTCA be used as a ‘rule in’ test rather than relying on 99th centile measures only? Applying early CCTA as a ‘rule in’ strategy in patients with NSTEACS at low-to-intermediate risk could improve the efficiency of catheterisation laboratories as only patients with significant coronary artery disease identified by CCTA would be triaged for invasive angiography. On its own, it is difficult to establish the benefit of a diagnostic modality like CCTA using an improvement in hard clinical outcomes. If performed promptly in emergency departments, the real utility of CCTA in patients with NSTEACS could lie in its ability to reduce the rate of downstream testing and the duration of antithrombotic medical therapy in patients without significant CAD. Additionally, by reducing the rate of downstream invasive coronary angiography the potential risks and complications associated with an invasive procedure could be avoided.

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