Systemic comparison of CT, IVUS and OCT to identify high-risk plaques

Overall, 379 histologic slices from nine coronary arteries of three donor hearts were available for analysis.²⁹⁸ Among the six histologic plaque types, pathologic intimal thickening (PIT) and fibrous plaques were most frequently detected (163 [43.0%] of 379 and 94 [24.8%]

of 379, respectively), followed by late fibroatheroma (LFA) (38 [10%] of 379), early fibroatheroma (EFA) (37 [9.8%] of 379), adaptive intimal thickening (AIT) (30 [7.9%] of 379), and thin-cap fibroatheroma (TCFA) (17 [4.5%] of 379). The proportion of cross-sections that

Figure 36 | The area under the receiver-operating characteristic curve was 0.678 for conventional plaque classification scheme (blue line) and 0.761 for plaque attenuation pattern (PAP) scheme (red line). The PAP scheme had a higher diagnostic performance than the conventional plaque scheme does, p=0.001.

showed early (AIT, PIT, fibrous plaque) versus advanced (EFA, LFA, TCFA) lesions was similar among the donor hearts (81%-71% vs. 19%-29%, respectively; p=0.45). All matched coronary CT angiography cross sections (n=379) were eligible for comparison with histologic findings; after 22.7% of IVUS and 24.8% of OFDI cross sections were excluded because of large vessel diameter, 293 IVUS and 285 OFDI cross sections remained available for analysis.

Additionally, we identified 57 distinct coronary lesions with a median of six cross sections (interquartile range, 4-8). Of these lesions, 29 were advanced and six contained TCFA.

Of the 379 coronary CT angiography cross sections, 91 (24.0%) were classified as showing normal findings, 157 (41.4%) as showing noncalcified plaque, 123 (32.5%) as showing mixed plaque, and only eight (2.1%) as showing calcified plaque (Table 19). Only 1.1% of normal coronary CT angiography cross sections contained an advanced lesion at

Table 19 Plaque composition as assessed by coronary computed tomographic angiography (CCTA), intravascular ultrasound (IVUS), and optical frequency domain imaging (OFDI) within atherosclerotic plaque categories as defined by histopathology.

Note: AIT, adaptive intimal thickening; PIT, pathological intimal thickening; Fib, fibrous plaques; EFA, early fibroatheroma;

LFA, late fibroatheroma; TCFA, thin-cap fibroatheroma; n, number of cross-sections.

histopathologic examination (negative predictive value: 98.9%; 95% CI: 94.1%, 99.9%). Most of the 91 normal cross sections at coronary CT angiography were fibrous plaques (48.4%), followed by AIT (28.6%) and PIT (22.0%) (Table 19). Accordingly, the normal coronary CTA cross sections were strongly associated with early plaque (OR=0.01, p=0.0006 [Table 20, Figure 37 A]). Most importantly, normal cross sections at coronary CT angiography excluded the presence of TCFA.

Of the 157 non-calcified cross sections at coronary CTA, 115 (73%) were classified as showing early atherosclerotic plaque at histologic examination, but that association was not significant (p=0.18). Notably, the coronary CTA category of non-calcified plaques contained nine TCFAs (5.7%). The presence of mixed plaque at coronary CTA (Figure 37 B) was associated with a significant increase in the odds of it being an advanced plaque (OR=4.71, p=0.0002). No association was observed between calcified plaques as defined at coronary CT angiography (n=8) and early (n=4) versus advanced (n=4) plaques at histologic examination

Table 20 Association of coronary computed tomographic angiography (CCTA), intravascular ultrasound (IVUS), and optical frequency domain imaging (OFDI) characteristics for early versus advanced plaque as defined by histopathology

Data represent absolute numbers. An OR >1.0 indicated an increased probability for being an advance lesion, whereas an OR

<1.0 indicated an increased probability for being an early lesion. Having several cross sections within one lesion, we derived OR and P values for clustered effect on a per-lesion basis. Owing to multiple testing, significance levels were adjusted by using Bonferroni correction. For modalities with four categories (CT, OFDI), P <0.0125 and for modalities with five categories (IVUS), P <0.01 was considered to indicate a significant difference. NA = not applicable.

(Table 20; Figure 37 C). Of the 293 IVUS images, six (2.0%) were classified as normal, seven (2.4%) as showing fibrous plaque, 119 (40.6%) as showing fibrofatty plaque, 82 (28.0%) as showing fatty plaque, and 79 (27.0%) as showing calcified plaque (Table 20). None of the normal IVUS cross sections was classified as showing an advanced plaque. The majority of fibro-fatty and fatty cross sections showed PIT or fibrous plaques, according to results of histologic examination (79.8% and 74.4%, respectively; Table 19, Figure 37 A). However, no significant association was found between fibro-fatty or fatty plaques and advanced plaque at histologic examination (Table 20). Cross sections categorized as calcified corresponded to advanced plaque at histologic examination in 36.7% (29/79) of cases. Thus, the presence of calcification at IVUS was associated in crude analysis with a significant increase in the odds of a plaque being advanced (OR=2.60, p=0.002), but this was attenuated marginally after

Figure 37 | A, Fibrous atherosclerotic plaque. The invasive modalities (OFDI and intravascular US) correctly depicted the fibrous plaque, whereas the coronary CT angiography cross section depicts normal vessel wall.

Arrows = eccentric intimal hyperplasia. B, LFA. Microcalcification (white arrows), a thick fibrous cap (black arrows), and necrotic core (*) are present. The corresponding cross section at OFDI was described as showing lipid-rich plaque with fibrous cap (arrows) and necrotic core (*). Intravascular US shows a fibro-fatty lesion with attenuated areas (*) corresponding to lipid-rich/necrotic areas. Coronary CT angiography depicts a mixed plaque with spotty calcification (arrows). C, TCFA. The necrotic core (*) is covered by a thin fibrotic cap;

arrows = sheet calcification. The corre- sponding cross section with OFDI reveals the TCFA, with lipid pool and large calcification. Intravascular US and coronary CT angiography show calcified plaques. C = catheter, L = lumen, SB = side branch.

accounting for clustered data structure (Table 20; Figure 37 C).

Of the 285 OFDI cross sections, zero (0%) were classified as normal, 157 (55.1%) as showing fibrous plaque, 58 (20.4%) as showing fibrocalcific plaque, and 70 (24.6%) as showing lipid-rich plaque (Table 19). Cross sections defined as showing fibrous plaque at OFDI corresponded to early plaque at histologic examination in 95.5% (150 of 157) of cases (Table 20; Figure 37 A) and were associated with small odds of representing advanced plaque (OR=0.04, p<0.0001; Table 20). The majority of fibrocalcific plaques as defined at OFDI were PIT or fibrous plaques at histologic examination (52 [89.7%] of 58); however, no association was detected between fibrocalcific plaque and histologic plaque stage (p=0.78; Table 20).

Notably, none of the fibrous, and fibrocalcific cross sections as defined at OFDI contained TCFA (Table 19). In contrast, lipid-rich plaque was found in 79.7% (51 of 64) of cross sections categorized as showing advanced plaque, corresponding to a high and significant odds ratio for the presence of advanced plaque at histologic examination (OR=57.15, P<0.0001; Table 20).

On a cross-section level, OFDI had a significantly better ability (both, p<0.0001) to differentiate early from advanced lesions as compared with IVUS and coronary CT angiography (areas under the curve: 0.858 [95% CI: 0.802, 0.913], 0.631 [95% CI: 0.554, 0.709], and 0.679 [95% CI:

0.618, 0.740], respectively; based on comparing 2 log likelihoods between nested models.

In a sub-analysis accounting for clustering effects, lipid-rich plaque as determined at OFDI yielded a sensitivity of 100% (95% CI: 75%, 100%) and a specificity of 81% (95% CI:

76%, 85%) for the detection of TCFA. In contrast, TCFA composition was heterogeneous and non-discriminatory at IVUS (predominantly fibrofatty, 63%) and coronary CTA (noncalcified plaque, 35%; mixed, 53%; calcified, 12%). In the assessment of individual lesions, OFDI had the best ability to discriminate between early and advanced lesions. The mean percentage of cross sections containing “lipid-rich plaque” was significantly higher in advanced compared with early lesions (43% vs 5%, p=0.04). At coronary CTA, the mean percentage of cross sections containing ”mixed plaque” was significantly higher in advanced compared with early lesions (46% vs 17%, p<0.01). Of note, 42% of early but only 6% of advanced lesions showed no plaque and thus were not detected at coronary CTA (p<0.05). In contrast, no significant difference was detected between the IVUS findings of early and advanced lesions.

The interobserver variability between the two coronary CTA readers for the four categories was excellent (Cohen k=0.87), with the majority of the disagreements occurring between classification as noncalcified plaque or normal vessel wall. The overall agreement between the two IVUS readers for the five plaque categories was good (Cohen k=0.66), but

grading of fibro-fatty versus fatty plaque and fibro-fatty versus fibrous plaque was inconsistent.

The interobserver variability between the two OFDI readers for the four plaque categories was excellent (Cohen k=0.85), with disagreement occurring mainly between fibrous and fibrocalcific plaque.