Diagnostic value of intraluminal stent enhancement in estimating coronary in-stent restenosis

INTRODUCTION

While coronary artery stent implantation is a gold standard approach for coronary arteries stenosis causing angina and/or myocardial infarction, in-stent restenosis (ISR) is the main complication of this approach occurring in 20–35% of bare-metal stents and only 5–10% for drug-eluting stents.^[1-3]

Coronary angiography is the standard approach for the assessment of ISR incidence and luminal stenosis severity that is an invasive procedure, posing considerable burden and costs in addition to its potential complications. Therefore, the requirement of a non-invasive means for ISR assessing is inevitably useful. Furthermore, gradual increase in number of patients undergoing coronary arteries stent placement better clarifies this requirement to minimize invasive procedures.^[4]

ISR diagnosis is the most challenging matter among patients with coronary artery disease (CAD) undergone stenting. Although coronary computed tomography angiography (CCTA) has been widely utilized for coronary arteries assessing, its efficacy for stent evaluation due to artifacts of stent struts, especially beam hardening and its narrow lumen, is still an important issue.^[5]

Multidetector CT (MDCT) introduction made a great revolution regarding coronary stent assessment as it could provide high-quality images with satisfactory temporal and spatial resolution. Furthermore, there are limitations including the type of stent (bare metal/drug eluting) and its diameter, stent strut thickness, its angularity, and motional artifacts in quality of these images.^[2,3,6,7]

The last versions of CT scans have more rapid imaging reception, higher spatial and temporal resolution and have particular software capable of coronary arteries and stent reconstruction led to less biases. Furthermore, by cardiac rate control and breath holding during imaging, the motion artifacts have been minimized.^[6]

Nowadays, most of CCTA reports are based on visual assessing of contrast flow of stent lumen while this method does not have ideal diagnostic value with significant interobserver biases. Quantitative measurements provide more reliable information about the status of stents. Recent studies have presented variety of quantitative methods with acceptable sensitivity and specificity for the diagnosis of ISR.^[8-10]

The current study has aimed to provide a quantitative method for ISR estimation, in which predictive value of stent enhancement in CCTA would be evaluated.

MATERIALS AND METHODS

RESULTS

Test results

Characteristics of implanted stents are presented in Table 1. Twenty-eight out of 58 cases (41.4%) were implanted in the left anterior coronary artery, 10 (17.2%) in the left circumflex artery, and 16 (27.6%) in the right coronary artery. Nine of stents had <3 mm of diameter, 26 of them had 3 mm of diameter, and other 23 ones had over 3 mm diameter.

Table 1: Characteristics of implanted stents.

Parameter	Total	ISR <50%	ISR 50%–100%	ISR 100%
Number of stents	58	39 (67.24%)	16 (27.58%)	3 (5.17%)
Location of stents
Left anterior descending artery	24 (41.4)	15 (41.7)	9 (56.3)	0
Left circumflex artery	10 (17.2)	5 (13.9)	2 (12.5)	1 (33.3)
Right coronary artery	16 (27.6)	12 (33.3)	3 (18.8)	1 (33.3)
Other	8 (13.8)	6 (11.1)	2 (12.5)	1 (33.3)
Stent diameter (mm)
<3	9 (15.5)	7 (17.94)	2 (12.5)	0
3	26 (44.8)	20 (51.28)	6 (37.5)	0
>3	23 (39.6)	12 (30.76)	8 (50)	3 (100)
Length (mm)	17.22±8.33 *	21.74±10.46*	25.87±12.52 *	27.33±4.61 *
Segment
Origin	2 (3.4)	1 (2.6)	1 (6.3)	0
Proximal	27 (46.6)	21 (53.8)	6 (37.5)	0
Proximal-middle	2 (3.4)	1 (2.6)	1 (6.3)	0
Middle	23 (39.7)	15 (38.5)	7 (43.8)	1 (33.3)
Middle-distal	1 (1.7)	0	0	1 (33.3)
Distal	3 (5.2)	1 (2.6)	1 (6.3)	1 (33.3)

*mean±SD

Among stents, 39 ones (67.24%) were patent or had ISR of <50%, 16 ones (2931%) had over 50% stenosis, and 3 ones (3.44%) were completely occluded.

The cutoff point for EV was measured in three sites of stents in CCTA images that were achieved based on CICA findings. These cutoff points were 204, 168, and 204 HU for initial, middle, and end part of stents, respectively, which show more than 50% of ISR. Mentioned cutoff points are presented in Table 2. Considering no statistical difference among these cutoff points (use 168 or 204) (P = 0.4), 168 HU was considered as the most valuable cutoff for the diagnosis of over 50% ISR due to its higher sensitivity and PPV [Figure 1].

Table 2: Sensitivity, specificity, positive predictive value, and likelihood ratio⁺ of EV and PCD for in-stent restenosis diagnosis.

Index	Cutoff point	Sensitivity (%)	Specificity (%)	Accuracy (%)	Likelihood ratio+	AUC	95% CI	P
PCD initial	500	79.49	63.16	74.14	2.15	0.69	0.53–0.85	0.404
EV initial	204	87	57.89	77.5	2.07	0.73	0.60–0.84
PCD mid	402	94.87	63.16	84.45	2.57	0.81	0.68–0.90	0.763
EV mid	168	92.3	73.68	86	3.5	0.85	0.68–0.90
PCD end	386	97.44	42	79.31	1.68	0.72	0.56–0.88	0.113
EV end	204	87	68	81	2.7	0.81	0.68–0.90

EV: Enhancement value, PCD: Post-contrast density

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Figure 1:

Comparison of diagnostic enhancement value in three sites of initial, middle, and end of stents.

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ISR was once measured based on stent intraluminal density just in post-contrast phase and then measured again using EV for comparison this method.

Table 2 shows validity, specificity, PPV, and diagnostic value based on stent intraluminal EV and also based on stent intraluminal density in post-contrast phase for ISR diagnosis, mentioned as post-contrast density (PCD). Comparison of PPV of EV method versus PCD showed superiority of EV method.

Considering area under curve (AUC) of all three above figures, EV is superior to PCD regarding its better predictive value [Figure 2].

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Figure 2:

Comparison of diagnostic value of in-stent restenosis diagnosis using enhancement value versus post-contrast density; (a) initial part of stent, (b) middle part of stent, and (c) end part of stent.

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As stent diameter may have impact on intraluminal density, ISR diagnostic value in EV method was assessed before and after stent diameter adjustment. Maximal 4–7% of decrease in three points of initial, middle, and end part of stent AUC were found that was negligible.

DISCUSSION

Stent implantation is one of the old and effective treatments of coronary artery stenosis while ISR is among the most significant complications of this approach.^[11,12] Incidence of restenosis is in association with factors including the type of stent (metallic or drug eluting), stent diameter and length, and the individual’s atherosclerotic factors such as diabetes.^[3,4] ISR diagnosis is made based on CICA. Although it is still the gold standard method of ISR diagnosis, its potential complications caused considerable trend toward non-invasive techniques.

Electron beam CT was the first non-invasive modality for stent status assessment introduced in 1995. In this method, it used images for flow-related analysis which showed flow limiting ISR indirectly. This method did not outlive due to its low spatial resolution, unavailability of direct stent lumen visualization, and inability for diagnosis non-obstructive intimal hyperplasia.^[13]

In the 1^st year of the 2000s, 4-slice CT scans were utilized, in which distal contrast runoff was the criterion of stent patency. These types of CTs were eliminated as well due to its low spatial and temporal resolution. Moreover, this technique was also affected by collateral vessels. By 16-slice CT scans introduction, stent lumen observation was possible and new windows of non-invasive stent luminal status assessment were opened toward physicians.^[2] This superiority is while factors including type of stent, its strut thickness, luminal diameter, and angle and motional artifacts can affect new CT scan modalities efficacy in negative manner. New generations of CT scans (e.g., 64, 128, and 320 slice) provide higher number of cuts with less thickness obtained in fewer time and they have some software for coronary artery and stent reconstruction with specific filters such as sharp kernel, therefore, they can better visualize stent’s lumen and provide more concise information about luminal status. Furthermore, new modalities provide reconstructed images with more clarified view of stents.^[13,14]

Qualitative stent patency assessment regarding intraluminal contrast flow has considerable interobserver bias, for narrow lumens in special. Quantitative method for luminal stenotic status estimation has better diagnostic values that have recently made them of great interest. In recent studies, various quantitative methods for ISR assessment such as corrected coronary opacification (CCO), remodeling index, lesion length, non-calcified lesion volume, and stent restenosis index (SRI) were introduced.^[8-10]

In most of quantitative methods mentioned above such as CCO introduced by Gao et al., in 2014,^[9] or SRI presented by Yoshimura et al., in 2015,^[8] coronary artery intraluminal density before and after stent was considered for patency assessment. Considering the fact that post-stent coronary artery intraluminal density would be affected by collateral vessels blood flow, direct stent luminal assessment seems superior.

SRI quantitative method was presented by Yoshimura et al., in which coronary artery intraluminal density before and after stent was measured and their difference based on luminal diameter correction was considered as stent stenotic status.^[8] In the current study, we used EV method and presented our outcomes following pre- and post-stent diameter adjustment. Regarding ROC curve, diagnostic values were not considerably improved. Therefore, we concluded that stent diameter is negligible but further studies to assess the impact of stent diameter on EV assessment are recommended.

The other quantitative method introduced by Kitagawa et al. utilized intraluminal density difference of proximal to stent site with stent itself. They presented 70 HU as the reliable cutoff point for over 50% of ISR.^[15]

Dr. Makoto Amanuma from Japan raised a novel method of ISR assessment, in which software for CT angiography subtraction has been used. The new method was accompanied with abilities including increased ISR diagnostic value and possibility of assessing stents with even <2.5 mm of diameter. In subtraction method, the final image will be achieved through comparison of images before and after contrast injection causing elimination of stent strut artifacts and calcified plaques. This superiority would be achieved in EV method introduced in our study as well.^[16] Furthermore, EV method gives us qualitative information with easier manner.

Considering this fact that basis of the most of the previous recommended quantitative methods for stent assessment was performed in post-contrast phase and this phase may be affected by confounding factors such as stent strut blooming artifacts and its plaques, we have selected EV method which is achieved through comparison of with and without contrast phases. Therefore, the mentioned bias may be eliminated.

Furthermore, in the current study, post-contrast intraluminal HU for the assessment of ISR was compared with EV as well. Statistical comparison of two techniques in initial, middle, and end sites showed no statistical differences, while PPV of EV method was considerably superior to post-contrast phase.

Eventually, the current study achieved remarkable successful outcomes in assessing ISR, for lumens with <3 mm diameter in special, using 256-slice CT scan. This achievement occurred due to high velocity, better spatial and temporal resolution, and using specific reconstruction filters.

CONCLUSION

The use of quantitative method of intraluminal stent enhancement for ISR estimation has better diagnostic value in comparison to qualitative and subjective methods that can help better clinical decision-making. Moreover, measurements of this method are somewhat easier and also secondary artifacts of stent strut and calcified plaques would be eliminated through EV method.