Introduction
The role of coronary computed tomography angiography (CCTA) in the evaluation of stable chest pain is an active area of research and debate. There have been multiple recent clinical trials, including SCOT-HEART, PROMISE, CONSERVE, and CRESCENT, that have added to the body of research supporting the role of CCTA as the first step in evaluation of these patients. This work has led the nation's largest commercial health insurer, United Healthcare, to recently update its reimbursement policies to cover CCTA as a "first line" test to assess stable chest pain in patients with low or intermediate risk for coronary artery disease (CAD).¹ Clinical guidelines in Europe have recommended CCTA first for stable chest pain for several years now, with the UK's National Institute for Health and Care Excellence (NICE) guidelines doing so in 2016 and the European Society of Cardiology (ESC) giving it a class I recommendation more recently in 2019.^2,3

The principal advantage of CCTA over stress testing is its ability to detect nonobstructive coronary atherosclerotic disease, which was associated with 77% of observed myocardial infarctions (MI) or deaths at follow up in the PROMISE trial. In addition to semi-quantifying coronary atherosclerotic plaque burden, CT technology also allows detecting and fully quantifying different types of coronary plaque. Despite conceptual challenges to the "vulnerable plaque" paradigm,⁴ there is continued interest in delineating plaque characteristics which may indicate risk of adverse events beyond disease burden. This review discusses the evidence in support of CCTA's role for the evaluation of patients with stable chest pain and the potential function of advanced plaque assessment in this context.

CCTA in Stable Chest Pain
The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10,003 low-risk, symptomatic patients to CCTA or stress testing (nuclear 68%, echo 22%, and exercise 10%).⁵ At 25 months, there was no difference in the primary composite outcome of death, MI, hospitalization for unstable angina, or major procedural complication (3.3% in CCTA group vs. 3% in stress group, P=0.75). CCTA was associated with more cardiac catheterizations at 90 days (12.2% vs. 8.1%) and greater overall radiation exposure (12.0 mSv vs. 10.1, P<0.001). There were 23% lower odds of MI with the CCTA strategy, but this was not statistically significant (95% confidence interval 0.48-1.23).⁶ Importantly, the PROMISE trial anticipated an event rate of 8% and the observed rate of 3% revealed that is was severely underpowered to show differences between the groups.

The SCOT-HEART trial enrolled 4,146 patients in Scotland with stable chest pain that were referred by the primary care physician to a cardiology clinic.⁷ During initial evaluation, nearly all patients underwent exercise stress testing (without imaging) and then were randomized to undergo CCTA or no CCTA within 14 days. At 1.7 years, the CT informed strategy was associated with a strong trend of lower risk of MI (1.1% vs. 1.7%, P=0.08) while death occurred at similar rates (0.8% vs. 1.0%, P=0.64). Several other trends were found, including more coronary revascularization procedures in the CCTA group (11.2% vs. 9.7%, P=0.06) than the control group. Compared with the standard of care, CCTA increased diagnostic certainty (RR 2.56, 95% CI 2.33–2.79, p<0.0001) and frequency (1.09, 1.02–1.17. p=0.0172) of the diagnosis of coronary heart disease at 6 weeks.

At 4.8 years, the two groups did not differ significantly in all-cause mortality (2.1% vs. 2.1%) or cardiovascular mortality (0.6% vs. 0.2%).⁸ However, the primary endpoint of death from coronary heart disease or nonfatal MI was significantly lower in the CCTA group than the control group (2.3% vs. 3.9%, HR 0.59, 95% CI 0.41-0.84). The disease specific mortality was statistically no different, leaving nonfatal MI (3.5% in CCTA group vs. 2.1% in standard care group, HR 0.60, 95% CI 0.41-0.87) alone to drive the significant difference in the primary outcome and thus the many headlines reporting that CCTA evaluation lowers long-term risk.⁹ The higher rates of invasive coronary angiography and coronary revascularization that were seen in the CCTA group at 1.7 years had become non-significant by 4.8 years. Notably, patients in the CCTA group were initiated on preventive therapies (19.4% vs. 14.7%, HR 1.40, 95% CI 1.19-1.65) and antianginal therapies (13.2% vs. 10.7%, HR 1.27, 95% CI 1.05-1.54) at significantly higher rates.

Even before the long-term SCOT-HEART results became available, combining data from these two trials suggested a 31% odds reduction for MI (95% confidence interval 0.49-0.99).⁶ These results were further strengthened by a large Danish registry involving 86,705 patients with stable chest pain who were followed after undergoing either CCTA or stress testing.¹⁰ Adjusted hazard for MI was 0.71 (95% confidence interval 0.61-0.82) and 0.87 (0.81-0.94) for the combined end point of all-cause death or MI. Thus, two randomized controlled trials and a large registry consistently revealed an approximately 30% risk reduction of MI with CCTA versus stress testing. The presumed mechanism of this risk reduction is the ability of CCTA to identify CAD at an earlier stage—undetectable by stress testing—which allows initiation of preventive measures otherwise not considered.

SCOT-HEART and Low-Attenuation Plaque
CCTA is capable of effectively visualizing, quantifying, and characterizing coronary atherosclerotic plaque. This has led to interest in identifying so called "high-risk" plaque – those lesions most likely to rupture and potentially lead to infarction.¹¹ A recent post-hoc analysis of the SCOT-HEART trial quantified plaque characteristics (total plaque, calcified, non-calcified, and low attenuation plaque) and compared those characteristics with coronary artery calcium scoring (CAC), observed coronary stenoses, and a cardiovascular risk prediction score (the ASSIGN score) in their ability to predict future MI at an average follow-up of 4.7 years.¹²

The authors found that low attenuation plaque best predicted risk of subsequent MI (HR 1.60, 95% CI 1.10-2.34) and added incrementally to the predictive power of CAC score, the ASSIGN risk score, and the presence of obstructive coronary disease. Patients with a low attenuation plaque burden of  >4% were five times more likely to suffer a fatal or non-fatal MI compared with those patients with less of a burden (HR 4.65, 95% CI 2.06-10.5). Interestingly, of the 1,769 patients initially included, only 41 experienced the primary outcome of fatal or non-fatal MI. This translates to an annualized event rate of 0.49%, which is remarkably low but consistent with prior studies.¹³ The study has been hailed as evidence of support for low attenuation plaque as a strong predictor of future events.

However, some limitations should be considered. Overfitting and collinearity, as evident from the large variability of hazard ratios among the models used by Williams et al., make it difficult to draw definitive conclusions. Furthermore, low attenuation plaque has been a variable predictor in other studies.¹⁴

Williams et al. show that patients were at greatest risk if they had obstructive disease as compared to no plaque at all, likely because it is a marker of advanced plaque burden.¹² Furthermore, a separate sub-study of the SCOT-HEART cohort found that patients with both obstructive disease and adverse plaque had the highest event rate, with a 10-fold increase in coronary heart disease death or nonfatal MI compared with patients with normal coronary arteries (HR 11.5, 95% CI 3.39-39.04, P< 0.001). However, these associations were not independent of coronary artery calcium score, a surrogate marker of global coronary plaque burden.¹⁴

The major advance enabled by CCTA versus stress testing is the ability to reliably identify coronary atherosclerotic disease at any stage and to implement effective prevention earlier in the process. It remains to be seen if there is indeed some incremental benefit of quantifying plaque characteristics for patient management.

CCTA: A Tool for Prevention
In light of this recent work, it remains our view that the most appropriate use of CCTA in these patients is in its ability to identify and quantify atherosclerotic disease to then effectively direct the intensity of prevention strategies through lifestyle improvements and risk factor control, rather than in an effort to characterize specific plaque subtypes. Rather than a win for plaque biology, the SCOT-HEART trial, similar to the PROMISE trial, represents a win for prevention.

The event rate in the SCOT-HEART trial of 41 MIs in 1,769 patients over nearly 5 years of follow-up is remarkably low and further evidence that prevention and medical management efforts and should be prioritized. With a 2.3% overall and an annualized event rate of about 0.5% at 5 years, we remain skeptical that studies with so few meaningful clinical events will move the needle on elevating specific plaque morphologies into clinical management conversations anytime soon. This is reminiscent of the PROMISE trial, which, as described above, enrolled 10,003 patients with stable chest pain. At just over 2 years of follow-up, the rate of major adverse cardiac events was only 3%.

Combined these two large studies raise the question – how do we identify those 1% of patients that are going to have atherosclerotic events each year? It is our view that currently we cannot do so with high accuracy. The pathophysiology of acute coronary events involves many poorly understood interactions between altered atherosclerotic plaque and a thrombosis-promoting milieu, which only in the "perfect storm" scenario can combine to result in a clinically relevant ischemic event. Because of the many variables involved, it remains difficult to predict a perfect storm.⁴

What we do know is that patients without imaging evidence of coronary atherosclerotic disease by CTA are at exceedingly low risk for adverse events. In addition to PROMISE and SCOT-HEART, data from more than 40,000 patients revealed a risk of less than 0.1% per year for MI or CV death.¹⁵ The risk remains close to zero for years after the CTA.¹⁶ We also know that the risk increases with increasing coronary atherosclerotic disease burden. Rather than focus on individual plaque characteristics to determine risk of future events, CCTA should be used to assess global burden of atherosclerotic disease and this should be followed by aggressive preventive care and risk factor modification.

We know that better control of blood pressure, lipids, exercise, and diet have a major impact on adverse cardiac events. However, despite clear evidence of the benefits of this secondary prevention, studies show that we significantly underperform in these efforts.¹⁷ Only half of those with hypertension have their blood pressure under control.¹⁸ A recent study found that only 58% of patients with established atherosclerotic cardiovascular disease use statins.¹⁹ Another study of patients post-MI found that one-fifth did not fill one of their cardiac medications, and half the time that medication was their antiplatelet therapy.²⁰ A recent "Call to Action" by the American Heart Association summed up the current state of care as, "Current CVD care remains far short of the evidence-based standard of care".²¹

The management of obstructive CAD in patients with stable chest pain is still being actively debated, with the recent ISCHEMIA trial revealing no outcome improvement with a routine invasive strategy. The results are not surprising given that coronary stenting does not address the (atherosclerotic) disease process but only mitigates its associated symptoms. PROMISE and SCOT-HEART taught us that identifying atherosclerotic disease earlier in the process leads to better outcomes. Remarkably, 77% of MIs and CV deaths in PROMISE occurred in patients with nonobstructive CAD by CCTA and 67% with normal stress test findings at baseline.²²

Yet, the management of non-obstructive CAD remains highly variable, with the majority of management of non-obstructive CAD being guided by non-cardiologists. Currently, there is not a clear framework for managing these patients who are often labeled as having "no significant CAD." This diagnosis of non-obstructive CAD is associated with diagnostic and therapeutic uncertainty, resulting in patients being less often treated with the appropriate secondary prevention therapies.²³ The presence of non-obstructive CAD, accounting for 55% of patients in PROMISE, represents an immense opportunity for aggressive prevention. In order for this opportunity to be capitalized upon, clear guidelines must be provided to cardiologists and non-cardiologists alike that label these patients as high risk and guide treatment with aggressive preventive therapies.

Both for non-cardiologists managing non-obstructive CAD and cardiologists managing obstructive CAD, CCTA represents one of the most powerful tools in the arsenal. To best use that tool, clear guidelines are required that guide next steps for intervention and prevention.

References

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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Dyslipidemias, Coronary Angiography, Coronary Artery Disease, Plaque, Atherosclerotic, Confidence Intervals, Insurance Carriers, Follow-Up Studies, Control Groups, Prospective Studies, Cardiovascular Diseases, Standard of Care, Calcium, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Platelet Aggregation Inhibitors, Risk Factors, Blood Pressure, Exercise Test, American Heart Association, Lipids, Physicians, Primary Care, Secondary Prevention

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