Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study

Background Unlike most noninvasive imaging modalities, coronary computed tomography angiography can characterize subtypes of atherosclerotic plaque. Objectives The purpose of this study was to investigate the prognostic implications of adverse coronary plaque characteristics in patients with suspected coronary artery disease. Methods In this SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) post hoc analysis, the presence of adverse plaque (positive remodeling or low attenuation plaque), obstructive disease, and coronary artery calcification within 15 coronary segments was assessed on coronary computed tomography angiography of 1,769 patients who were followed-up for 5 years. Results Among study participants (mean age 58 ± 10 years; 56% male), 608 (34%) patients had 1 or more adverse plaque features. Coronary heart disease death or nonfatal myocardial infarction was 3 times more frequent in patients with adverse plaque (n = 25 of 608 [4.1%] vs. n = 16 of 1,161 [1.4%]; p < 0.001; hazard ratio [HR]: 3.01; 95% confidence interval (CI): 1.61 to 5.63; p = 0.001) and was twice as frequent in those with obstructive disease (n = 22 of 452 [4.9%] vs. n = 16 of 671 [2.4%]; p = 0.024; HR: 1.99; 95% CI: 1.05 to 3.79; p = 0.036). 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 myocardial infarction compared with patients with normal coronary arteries (HR: 11.50; 95% CI: 3.39 to 39.04; p < 0.001). However, these associations were not independent of coronary artery calcium score, a surrogate measure of coronary plaque burden. Conclusions Adverse coronary plaque characteristics and overall calcified plaque burden confer an increased risk of coronary heart disease death or nonfatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590)

T he investigation of patients with suspected coronary artery disease has previously focused on functional assessments that attempt to identify the presence of myocardial ischemia as a downstream surrogate marker of proximal coronary artery stenoses. In contrast, noninvasive imaging with coronary computed tomography angiography (CTA) has the ability to provide precise structural information of the coronary artery wall, and can assess for the presence and constituents of atherosclerotic plaque even in the absence of flowlimiting disease.
Pathological studies in patients with myocardial infarction have identified an association between plaque rupture and adverse plaque characteristics that includes positive remodeling, a large necrotic core, microcalcification, and a thin fibrous cap (1).
Correlates of these features have been described for noninvasive imaging with coronary CTA and include the presence of positive remodeling, low attenuation plaque, spotty calcification, and the "napkin ring" sign (2).
These plaque characteristics are associated with an increased risk of subsequent acute coronary syndromes (2)(3)(4). Recent data have suggested that positive remodeling and low attenuation plaque in particular provide the most useful prognostic information (2,5), although it remains unclear whether this is of incremental value to traditional cardiovascular risk factors or coronary plaque burden.
In the SCOT-HEART (Scottish COmputed Tomography of the HEART) prospective, multicenter, randomized controlled trial of patients with stable chest pain, the addition of coronary CTA to routine care led to improved diagnostic certainty and patient care that ultimately reduced the rate of coronary heart disease death or nonfatal myocardial infarction (6)(7)(8). These benefits were largely attributable to subsequent changes in patient management and treatment, which had been guided by the presence of obstructive or nonobstructive coronary artery disease as determined by coronary CTA. However, it may be that further risk stratification and targeted intensification of therapy in patients with adverse plaque characteristics could achieve additional benefits that go beyond the presence of obstructive or nonobstructive coronary artery disease.
In this secondary analysis of the SCOT-HEART trial, we aimed to determine the extent of adverse coronary artery plaque characteristics on coronary CTA and their association with subsequent clinical outcomes. If confirmed, the identification of these coronary artery plaque characteristics may help risk stratification and guide the intensity of therapy.

METHODS
STUDY DESIGN. The SCOT-HEART trial was a multicenter randomized controlled trial of coronary CTA in outpatients with suspected angina pectoris due to coronary artery disease (9). The primary results have been reported previously (6)(7)(8). This paper presents a secondary post hoc analysis of the SCOT-HEART study.
PARTICIPANTS. In brief, 4,146 patients who attended the cardiology outpatient clinic were randomized to standard care alone or standard care plus coronary CTA, and were followed up for symptoms, management, and outcomes. Of the 2,073 participants who were randomized to the intervention arm, 1,778 underwent coronary CTA. Coronary CTA and noncontrast imaging for calcium scoring was performed as described previously (7). Cardiovascular risk was assessed using the ASSIGN (ASsessing cardiovascular risk using Scottish Intercollegiate Guideline Network guidelines) score. This score has been validated for the Scottish population and, in addition to traditional cardiovascular risk factors, incorporates social deprivation and family history of cardiovascular disease (10).

ASSESSMENT OF COMPUTED TOMOGRAPHY IMAGES.
Coronary artery calcium score was assessed on noncontrast computed tomography (CT) using the Agatston scoring method as previously described (11 For each segment, the presence or absence of 4 coronary artery plaque characteristics was assessed ( Figure 1): positive remodeling, low attenuation plaque, spotty calcification, and the "napkin ring" sign.
Positive remodeling was defined as an outer vessel diameter that was 10% greater than the mean of the diameter of the segments immediately proximal and distal to the plaque (3). Low-attenuation plaque was defined as a focal central area of plaque with an attenuation density of <30 Hounsfield Units (14).
Spotty calcification was defined as focal calcification within the coronary artery wall <3 mm in maximum diameter (3). The "napkin ring" sign was defined, as previously described, as a central area of lowattenuation plaque that had a peripheral rim of high attenuation (15). Observer agreement for the assessment of coronary artery plaque characteristics has overall been shown to be fair (16).   Low-attenuation plaque (B) was defined as a focal central area of plaque with an attenuation density of <30 Hounsfield Units (yellow arrow). Spotty calcification (C) was defined as focal calcification within the coronary artery wall that measured <3 mm in maximum diameter (yellow arrow). The "napkin ring" sign (D) was defined as a central area of low-attenuation plaque with a peripheral rim of high attenuation (yellow arrow). The assumption of proportional hazards was checked using SPSS. A statistically significant difference was defined as a 2-sided p value <0.05.

RESULTS
Of the 1,778 individuals who underwent a coronary CTA, 1,769 participants had images that were available and of suitable quality for analysis (Online Figure 1).
Patients had a mean age of 58 AE 10 years, and 56% were male with a range of cardiovascular risk factors and symptoms ( Table 1). Of these patients, 37% (n ¼ 646) had normal coronary arteries, 38% (n ¼ 671) had nonobstructive coronary artery disease, and 26% Adverse plaques were present in 608 (34%) patients. Patients with adverse plaques were older, had a higher body mass index, and were more likely to be male. They were also more likely to have a previous history of coronary heart disease or hypertension, to be a smoker, or to have typical angina ( Table 1, Online   >30 kg/m 2 or with a lower cardiovascular risk score, but these differences were not statistically significant (Online Table 6). The presence of 1 or more segments of spotty calcification or the napkin ring sign was not associated with a difference in coronary heart disease death or nonfatal myocardial infarction on perpatient assessment (Online Tables 3 and 7). Indeed, compared with patients with normal coronary arteries, patients with obstructive disease and adverse plaque had a >10-fold increase in the rate of coronary heart disease death or nonfatal myocardial infarction at 5 years ( Table 3).
CORONARY ARTERY CALCIUM SCORE. Patients with a coronary artery calcium score $1,000 AU had a 13-fold increase in coronary heart disease death or nonfatal myocardial infarction compared with Coronary Artery Plaque Characteristics  Cumulative incidence plot for coronary heart disease death and nonfatal myocardial infarction in patients (top) with normal coronary arteries, nonobstructive disease, and obstructive disease and in (bottom) normal coronary arteries, nonobstructive disease with and without adverse plaque characteristics, and obstructive disease with and without adverse plaque features. AP ¼ adverse plaque; other abbreviations as in Figure 2.
Williams et al. Coronary Artery Plaque Characteristics J A N U A R Y 2 9 , 2 0 1 9 : 2 9 1 -3 0 1 patients without coronary artery calcification. There was a clear gradation of risk, with calcification associated with increasing risk (Figure 4)  of the atherosclerotic plaque rather than the functional consequence of luminal stenosis (26). For the prediction of subsequent coronary events, the presence of atherosclerotic plaque is more important than the presence of coronary stenoses. Indeed, in our study, patients with a combination of both obstructive coronary artery disease and adverse plaque had the worst outcomes. Moreover, patients with nonobstructive disease and adverse plaque had similar outcomes to patients with obstructive disease without adverse plaque. Thus, our study provides evidence that coronary artery disease should no longer be defined based on luminal severity, but instead by the volume and type of disease.
When examined across the cohort as a whole, adverse plaques did not provide independent prognostic information when CT calcium scoring was included. CT calcium scoring is a surrogate marker of plaque burden, and its prognostic utility has been established in large studies of symptomatic and asymptomatic patients (27,28). It is likely that pa- Cumulative incidence plots of the effect of different severity of coronary artery calcification on subsequent coronary heart disease death or nonfatal myocardial infarction. Abbreviations as in Figure 2.

CONCLUSIONS
We have demonstrated that adverse plaque characteristics provide prognostic information out to 5 years, but that this is not independent of plaque burden assessed by coronary artery calcium score.
Patients with obstructive disease and adverse plaques have the highest event rates throughout follow-up.
This may aid the identification of a subgroup of patients who would benefit from more intensive medical therapy.