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Association between coronary artery calcium score and in-stent restenosis after drug-eluting stent implantation

Association between coronary artery calcium score and in-stent restenosis after drug-eluting... 284 Original article Association between coronary artery calcium score and in-stent restenosis after drug-eluting stent implantation Xiaowen Zheng*, Ke Xu*, Xiaoxiao Yang, Wentao Yang, Weifeng Zhang, Yue Jiang, Yipeng Zhang, Xingbiao Qiu, Hongyu Shi, Lisheng Jiang, Linghong Shen, and Ben He Background Coronary artery calcium (CAC) is a specificity, 91.9%; area under the curve, 0.704; P < 0.001). modifiable contributor of in-stent restenosis (ISR), but Multivariable logistic regression models indicated a quantitative analyses using a noninvasive approach are CAC score >245 in CCTA/2.5 mm group and >209 in limited. We aimed to investigate the associations between NCCT/5 mm group independently associated with an 8.46- CAC score derived from ECG-gated coronary computed and 21.89-fold increase in ISR, respectively (all P < 0.01). tomography angiography (CCTA) or non-gated non- Conclusions Either a CAC score >245 in CCTA/2.5 mm contrast chest computed tomography (NCCT) and ISR. or >209 in NCCT/5 mm was significantly associated Methods We included 368 lesions in 194 patients with increased risk in ISR. Coron Artery Dis 33: 284–294 with coronary drug-eluting stent implantations in final Copyright © 2022 The Author(s). Published by Wolters analyses. CAC was quantified using the Agatston score. Kluwer Health, Inc. Primary endpoint was ISR, defined as lumen diameter Coronary Artery Disease 2022, 33:284–294 stenosis over 50% at the stent segment or its proximal or Keywords: coronary artery calcium, coronary computed tomography distal edges (5-mm segments adjacent to the stent), at angiography, in-stent restenosis, nongated noncontrast chest computed angiographic follow-up. tomography, percutaneous coronary intervention Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong Results The CAC scores in either CCTA/2.5 mm group University, Shanghai, China (r = 0.7702; P < 0.0001) or NCCT/5 mm group (r = 0.7105; P < 0.0001) were both correlated with in-stent diameter Correspondence to Dr. Linghong Shen, MD, PhD, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai stenosis. The receiver-operating characteristic curve Road, Shanghai, 200030, China analysis identified a CAC score >245 in CCTA/2.5 mm Tel: +86 21 22200000; e-mail: rjshenlinghong@126.com. group as the optimal ISR cutoff (sensitivity, 60.0%; *Dr. Xiaowen Zheng and Dr. Ke Xu are considered as co-first authors. specificity, 83.7%; area under the curve, 0.744; P < 0.001), Received 15 June 2021 Accepted 12 December 2021 and >209 in NCCT/5 mm group (sensitivity, 46.7%; Introduction According to the results from studies of intravascular In-stent restenosis (ISR) is well recognized as a clinically imaging, stent expansion is mainly associated with the significant complication after coronary stent implantation, angle, length and thickness of calcium deposition. Using observed in 20–30% of patients undergoing bare-metal intravascular ultrasound (IVUS), stent expansion was stent implantation and 5–15% undergoing drug-eluting found to be inversely correlated with the arc of calcium stent (DES) implantation [1,2]. It may be due to bio- [4]. An optical coherence tomography (OCT)-based cal- logic, mechanic or technical factors [3]. Of these, stent cium scoring system further demonstrated that lesions under-expansion plays an important role and coronary with a maximum angle greater than 180°, maximum artery calcium (CAC) has been recognized as a major thickness more than 0.5 mm and length more than 5 mm determinant of stent underexpansion during the percu- would be at risk of stent underexpansion [5]. Although taneous coronary intervention (PCI). Thus, an accurate it was generally agreed that coronary angiography was evaluation of CAC is of clinical significance in planning less sensitive to detect CAC compared to intravascular a PCI strategy. imaging, Wang et al., [6] recently reported that angio- graphically invisible calcium (only detectable by IVUS or OCT) did not appear to inhibit stent expansion and angi- Supplemental Digital Content is available for this article. Direct URL citations ographically visible calcium seemed to be a good marker appear in the printed text and are provided in the HTML and PDF versions of this for predicting stent underexpansion [6]. It might be article on the journal’s website, www.coronary-artery.com. because some of the angiographically invisible calcium This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- were thinner (<0.50  mm) in thickness, which is associ- NC-ND), where it is permissible to download and share the work provided it is ated with a greater stent expansion because of calcium properly cited. The work cannot be changed in any way or used commercially fracture during PCI [7,8]. Therefore, the evaluation of without permission from the journal. 0954-6928 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/MCA.0000000000001124 CAC score for ISR after DES implantation Zheng et al. 285 calcium density and total volume is imperative for pre- coronary angiography (QCA). We assumed that ISR in dicting stent expansion. the vessel with reference diameter below 2.5  mm may be mainly caused by a small in-stent lumen diameter but Computed tomography (CT) is the only noninvasive not CAC. modality with high sensitivity and specificity for cal- cium detection. Usually, the severity of CAC assessed Study endpoints by CT images is quantified with a method introduced by The primary endpoint of this study was ISR at angio- Agatston et al., [9] called the Agatston score. It takes into graphic follow-up, defined as lumen diameter stenosis account both the area and peak density of calcified lesions. over 50% at the stent segment or its proximal or distal Previous studies have suggested that the Agatston score edges (5-mm segments adjacent to the stent) [13]. We correlates to late lumen loss [10] and might be helpful in assessed lumen diameter stenosis and late lumen loss by determining the treatment strategy for complex coronary QCA, that is, diameter stenosis = (reference vessel diam- artery lesions with severe calcification [11]. However, the eter − minimal lumen diameter)/reference vessel diame- exact relationship between the calcium score and ISR is ter × 100%), and late lumen loss = postprocedural minimal not well understood. lumen diameter − minimal lumen diameter at follow-up. Target lesion revascularization (TLR) was also recorded Traditionally, Agatston-score assessment is based on ECG-gated coronary CT angiography (CCTA) [9]. with medical chart review. However, nongated noncontrast chest CT (NCCT) is more technically simple and widely used in routine prac- Quantitative coronary angiography analysis tice compared with CCTA. Previous studies have illus- QCA was performed following the standard proce- trated a high correlation between NCCT and CCTA for dure of analysis using a validated software (QAngio CAC quantification [12]. However, the utility of CAC XA 7.3, Medis Medical Imaging Systems, Leiden, the quantification using NCCT for predicting ISR after cor - Netherlands). QCA was analyzed by two independent, onary stent implantation has not been well described. well-trained technicians who had performed QCA in at Moreover, a clinically useful cutoff value of CAC severity least 50 patients, who were blinded with data on CAC for optimizing interventional strategy to reduce ISR risk score. Case examples were present in Supplementary has not been well determined. Figure S1–S6, Supplemental digital content 1, http://links. lww.com/MCA/A484. Accordingly, we performed this study to explore the asso- ciations between CCTA- or NCCT-derived CAC score Computed tomography and coronary artery calcium and ISR. quantification Images of CCTA or NCCT were acquired using sin- Methods gle-source ≥64-row CT scanners. Using reproducible land- Study design marks such as the ostium of main vessel and side branches, This single-center, retrospective study was conducted in the target segment undergoing PCI was determined on Shanghai Chest Hospital, Shanghai Jiao Tong University, images of CCTA or NCCT with the use of angiographic following the principles of the Declaration of Helsinki images as a reference. Scans were interpreted by two and local regulations. This study was approved by the investigators independently, who were blinded with data ethics committee of Shanghai Chest Hospital, Shanghai on QCA analyses. CAC was quantified using the Agatston Jiao Tong University. Written informed consents were method [9] with a commercially available software (OsiriX, waived. Pixmeo SARL, Bernex, Switzerland). Case examples were present in Supplementary Figure S1–S6, Supplemental Study population digital content 1, http://links.lww.com/MCA/A484. We retrospectively screened patients (≥18 years) under- going DES implantation for de novo coronary lesions in the Department of Cardiology, Shanghai Chest Hospital, Statistical analyses Shanghai Jiao Tong University from January 2010 to Descriptive statistics are presented as mean ± SD, median January 2020. We enrolled patients who had documented (interquartile range) or number (percentage) as appropri- coronary angiographic images at both index procedure ate. Data were presented on a per-patient basis for clini- and follow-up after 6–18 months and received a CT (i.e. cal characteristics and per-vessel basis for the remaining NCCT or CCTA) scan within 3 months before index pro- analyses. We compared target lesion and procedural char- cedure. Exclusion criteria were ST-segment-elevation acteristics and angiographic parameters before and after myocardial infarction, prior coronary artery bypass graft- the index procedure and at the angiographic follow-up ing, chronic renal failure, hemodialysis, or metal implants between groups with the use of unpaired Student’s t-test, affecting CAC quantification. Angiographic exclusion cri- Mann–Whitney U tests or chi-square tests as appropri- teria were stent fracture or reference vessel diameter of ate. The lesion CAC score was correlated with in-stent, the target lesion below 2.5 mm assessed by quantitative proximal-edge and distal-edge diameter stenosis and 286 Coronary Artery Disease 2022, Vol 33 No 4 lumen late loss. CAC score in lesions with ISR was com- follow-up. Age greater than 65 years, male sex, hyperlipi- pared with that in the lesion with no ISR with the use of demia, smoking, stent diameter and stent length were Mann–Whitney U tests. Considering that (1) CCTA with included in multivariable analyses. 2.5-mm detector row width (CCTA/2.5 mm) and NCCT All analyses were conducted with the STATA software with 5-mm detector row width (NCCT/5  mm) account version 14.0 (Stata Corp, College Station, Texas, USA) for the highest percentage of included lesions and and GraphPad Prism version 5.0.1 (GraphPad Software, patients as shown in Table  1 (indicating that these two San Diego, California, USA). A two-sided P value of types of CT scan may be the mostly used in clinical prac- <0.05 was considered statistically significant. tice) and (2) we recognized that the detector row width of CT scan may affect the cutoff value, we chose to perform Results subgroup analyses in lesions receiving CCTA/2.5  mm Baseline clinical, lesion and procedural characteristics (168 lesions in 90 patients) and NCCT/5 mm scans (138 We screened 5158 patients receiving DES implantation. lesions in 71 patients) and generated specific cutoff Finally, 368 lesions in 194 patients which met the inclu- values for each type of the CT scan. We set the lesions sion criteria and had none of the exclusion criteria were with CAC score = 0 as the reference group, and divided included in the analyses (Fig.  1). The demographic and the lesions with CAC score > 0 into quartiles. We com- clinical characteristics of the patients are summarized in pared the in-stent diameter stenosis and late lumen loss Table  1. The mean age of patients was 67.2 ± 8.5 years, among groups with different CAC scores with the use and 70.1% were male. Ninety-five patients received the of one-way analysis of variance followed by Dunnett’s NCCT scan. Of these, 71 had NCCT with 5-mm detec- tests using the group with CAC score = 0 as the reference tor row width and 24 with ≤3-mm detector row width. group. Divided by the cutoff point of the CAC score, Ninety-nine patients received the CCTA scan. Of these, target lesion and procedural characteristics and angio- 90 had CCTA with 2.5-mm detector row width and 9 with graphic parameters before and after the index proce- ≤1.5-mm detector row width. The demographic and clin- dure and at the angiographic follow-up were compared ical characteristics of the patients in the CCTA/2.5  mm as described above in the CCTA/2.5  mm group or the group and NCCT/5  mm group are summarized in NCCT/5  mm group. A receiver-operating characteristic Supplementary Table S1, Supplemental digital content (ROC) curve analysis was used to determine the ability 1, http://links.lww.com/MCA/A484. The percentage of of the lesion CAC score to distinguish between lesions patients with the acute coronary syndrome (i.e. unstable with and without ISR at angiographic follow-up and angina or non-ST-segment elevation myocardial infarc- identify the optimal cutoff point of the lesion CAC score tion) in the NCCT/5 mm group was higher than that in that provided the greatest sum of sensitivity and spec- the CCTA/2.5 mm group. Other baseline characteristics ificity in the CCTA/2.5  mm group or the NCCT/5  mm were comparable. The baseline lesion and procedural group, respectively. Univariable and multivariable logis- characteristics are presented in Table  2. Half (49.5%) of tic regression models were performed to determine the target lesions were located at the left anterior descending association between CAC score and ISR at angiographic artery, 20.6% at the left circumflex artery and 29.9% at the right coronary artery. The median CAC score was 32, and the minimal and maximal scores were 0 and 1085, Table 1. Baseline clinical characteristics of all patients included in analyses (n = 194). respectively. Two patients received advanced techniques for severe CAC. One with a CAC score of 307 received Characteristics cutting balloon inflation, and the other with a CAC score Age, years 67 .2 ± 8.5 of 272 received rotational atherectomy. Most lesions Male sex 136 (70.1) Diagnosis (78.3%) were treated by implanting a sirolimus-elut- Stable angina or silent ischemia 104 (53.6) ing stent. The mean stent diameter and length were Unstable angina 53 (27.3) 3.0 ± 0.4  mm and 27.5 ± 7.3  mm, respectively. T able  2 Non-ST-segment elevation myocardial infarction 37 (19.1) Hypertension 142 (73.2) presents the angiographic characteristics of target lesions Diabetes mellitus 77 (39.7) at index procedure and follow-up. The mean duration Hyperlipidaemia 138 (71.1) Smoking 111 (57.2) between the index procedure and angiographic follow-up Multivessel disease was 12.8 ± 5.4 months. Preprocedural diameter stenosis of 1 vessel 61 (31.4) 2 vessels 70 (35.6) the target lesion was (72.8 ± 14.5)%, and in-stent diam- 3 vessels 63 (33.0) eter stenosis was (9.9 ± 4.2)% after the procedure and Type of CT/detector row width (22.8 ± 17.4)% at angiographic follow-up. Thirty-two CCTA/≤1.5 mm 9 (4.6) CCTA/2.5 mm 90 (46.4) (8.7%) lesions received TLR at the angiographic fol- NCCT/≤3 mm 24 (12.4) low-up. The procedural and angiographic characteristics NCCT/5 mm 71 (36.6) of the CCTA/2.5-mm and NCCT/5-mm groups were Values are mean ± SD or n (%). present in Supplementary Table S2–S5, Supplemental CCTA, coronary computed tomography angiography; CT, computed tomography; digital content 1, http://links.lww.com/MCA/A484. NCCT, noncontrast chest computed tomography. CAC score for ISR after DES implantation Zheng et al. 287 Fig. 1. Study flow diagram. CABG, coronary artery bypass grafting; CAC, coronary artery calcium; CCTA, coronary computed tomographic angiography; DES, drug-eluting stent; NCCT, noncontrast chest computed tomography; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; STEMI, ST-segment elevation myocardial infarction. Coronary artery calcium score, diameter stenosis, late Coronary artery calcium score, in-stent diameter lumen loss and in-stent restenosis stenosis and in-stent restenosis in lesions receiving the In Fig. 2, the lesion CAC score was significantly correlated noncontrast chest computed tomography/5 mm scan with in-stent diameter stenosis (Spearman r = 0.7357; In the NCCT/5  mm group, the lesion CAC score was P < 0.0001) but not proximal-edge (Spearman r = 0.0724; significantly correlated with in-stent diameter stenosis P = 0.17) or distal-edge diameter stenosis (Spearman (Spearman r = 0.7105; P < 0.0001; Fig. 3). In-stent diame- r = 0.0762; P = 0.14) assessed at angiographic follow-up. ter stenosis and late lumen loss were significantly higher The lesion CAC score was significantly correlated with in lesions with CAC scores of 23–67, 68–192, or >192 in-stent (Spearman r = 0.7306; P < 0.0001), proximal-edge than those with a CAC score of 0 (all P < 0.05; T able  3; (Spearman r = 0.1931; P = 0.0002) and distal-edge late Fig. 4). Among the 138 lesions in the NCCT/5 mm group, lumen loss (Spearman r = 0.2136; P < 0.0001). Among the 15 (10.9%) had ISR. Lesions with ISR had significantly 368 lesions, 32 (8.7%) had ISR. Lesions with ISR had sig- higher CAC scores than those with no ISR [130 (28, 325) nificantly higher CAC scores than those with no ISR [189 vs. 10 (0, 96); P = 0.0082). (28, 512) vs. 29.5 (0, 131.5); P = 0.0002]. No ISRs were observed in patients who received advanced techniques. Receiver-operating characteristic analyses In the CCTA/2.5  mm group, the ROC curve analysis Coronary artery calcium score, in-stent diameter demonstrated that a lesion CAC score distinguishes stenosis and in-stent restenosis in lesions receiving the between ISR and non-ISR [area under the curve, 0.744; coronary computed tomography angiography/2.5 mm 95% confidence interval (CI), 0.602– 0.886; P = 0.002; scan Fig.  5a]. The lesion CAC score greater than 245 was In the CCTA/2.5  mm group, the lesion CAC score was identified as the optimal cutoff value providing the great- significantly correlated with in-stent diameter stenosis est sum of sensitivity (60.0%; 95% CI, 32.4–83.7%) and (Spearman r = 0.7702; P < 0.0001; Fig. 3). In-stent diame- specificity (83.7%; 95% CI, 76.8– 89.1%). Lesions with a ter stenosis and late lumen loss were significantly higher CAC score greater than 245 had higher residual diam- in lesions with CAC scores of 26–87, 88–220 or >220 than eter stenosis after the procedure and in-stent minimal those with a CAC score of 0 (all P < 0.05; Table 3; Fig. 4). lumen diameter, in-stent diameter stenosis and in-stent Among the 168 lesions in the CCTA/2.5  mm group, late lumen loss at angiographic follow-up as compared 15 (8.9%) had ISR. Lesions with ISR had significantly with those with CAC score ≤245. In the 34 lesions with higher CAC scores than those with no ISR [251 (43, 620) a CAC score greater than 245, 9 (26.5%) had ISR, and vs. 47 (5, 176.5); P = 0.0019). in the 134 lesions with a CAC score ≤245, 6 (4.5%) had 288 Coronary Artery Disease 2022, Vol 33 No 4 Table 2. Baseline lesion, procedural, angiographic characteristics of target lesions at index procedure and follow-up, stratified by coro- nary artery calcium score Overall (n = 368) CAC score = 0 (n = 94) CAC score > 0 (n = 274) P value Baseline lesion and procedural characteristics Location of target lesions 0.010 LAD 182 (49.5) 34 (36.2) 148 (54.0) LCx 76 (20.6) 23 (24.5) 53 (19.3) RCA 110 (29.9) 37 (39.4) 73 (26.6) CAC score 32 (0, 153.8) 0 67 (22, 192.5) <0.001 ACC/AHA classification 0.001 A 29 (7.9) 10 (10.6) 19 (6.9) B 120 (32.6) 43 (45.8) 77 (28.1) C 219 (59.5) 41 (43.6) 178 (65.0) TIMI flow at baseline 0.41 0 25 (6.8) 3 (3.2) 22 (8.0) 1 27 (7.3) 6 (6.4) 21 (7.7) 2 113 (30.7) 30 (31.9) 83 (30.3) 3 203 (55.2) 55 (58.5) 148 (54.0) Stent type 0.24 Sirolimus-eluting stent 288 (78.3) 69 (73.4) 219 (79.9) Zotarolimus-eluting stent 48 (13.0) 13 (13.8) 35 (12.8) Everolimus-eluting stent 32 (8.7) 12 (12.8) 20 (7.3) Stent diameter, mm 3.0 ± 0.4 2.9 ± 0.4 3.0 ± 0.4 0.26 Stent length, mm 27 .5 ± 7 .3 27 .3 ± 7 .5 27 .6 ± 7 .2 0.75 Maximal balloon pressure, atm 18.5 ± 3.8 16.9 ± 3.1 19.1 ± 3.9 <0.0001 Angiographic characteristics of target lesions at index procedure and follow-up Before procedure Minimal lumen diameter, mm 0.8 ± 0.4 0.8 ± 0.4 0.8 ± 0.5 0.22 Reference vessel diameter, mm 2.9 ± 0.4 2.9 ± 0.4 2.9 ± 0.4 0.78 Diameter stenosis, % 72.8 ± 14.5 70.8 ± 13.2 73.4 ± 14.9 0.14 Length of target lesions, mm 22.4 ± 7 .2 21.5 ± 7 .2 22.7 ± 7 .2 0.16 After procedure Minimal lumen diameter, mm Proximal 3.0 ± 0.5 3.0 ± 0.5 3.1 ± 0.6 0.27 In-stent 2.8 ± 0.4 2.8 ± 0.4 2.8 ± 0.4 0.20 Distal 2.5 ± 0.5 2.5 ± 0.5 2.5 ± 0.5 0.58 Residual diameter stenosis, % Proximal 7 .1 ± 7 .4 7 .2 ± 6.7 7 .1 ± 7 .7 0.91 In-stent 9.9 ± 4.2 7 .4 ± 2.4 10.8 ± 4.4 <0.001 Distal 8.7 ± 8.0 9.1 ± 7 .9 8.6 ± 8.0 0.56 Follow-up Minimal lumen diameter, mm Proximal 2.9 ± 1.1 3.1 ± 1.8 2.8 ± 0.7 0.012 In-stent 2.2 ± 0.6 2.6 ± 0.5 2.1 ± 0.6 <0.001 Distal 2.3 ± 0.6 2.4 ± 0.5 2.3 ± 0.6 0.038 Diameter stenosis, % Proximal 10.5 ± 15.5 9.2 ± 15.5 11.0 ± 15.5 0.33 In-stent 22.8 ± 17 .4 12.7 ± 11.3 26.3 ± 17 .8 <0.001 Distal 12.0 ± 13.1 9.7 ± 10.2 12.8 ± 13.8 0.052 Late lumen loss, mm Proximal 0.2 ± 1.0 −0.1 ± 1.8 0.3 ± 0.5 0.001 In-stent 0.5 ± 0.5 0.2 ± 0.4 0.6 ± 0.5 <0.001 Distal 0.2 ± 0.5 0.1 ± 0.4 0.3 ± 0.5 0.060 Target lesion revascularization 32 (8.7) 4 (4.3) 28 (10.2) 0.077 Values are mean ± SD, median (interquartile range), or n (%). CAC score was calculated using the Agatston score. P values were calculated for the comparison between groups with CAC score = 0 and CAC score >0 with the use of unpaired Student t-tests, Mann–Whitney U tests, or chi-square tests as appropriate. ACC/AHA, American College of Cardiology/American Heart Association; CAC, coronary artery calcium; LAD, left anterior descending artery; LCx, left circumflex artery; RCA, right coronary artery; TIMI, Thrombolysis In Myocardial Infarction. ISR. The risk of ISR was significantly higher in lesions score >245 in lesions in the CCTA/2.5  mm group was with a CAC score >245 than in those with a CAC score identified to be independently associated with a higher risk in ISR at the angiographic follow-up. Lesions with a ≤245 (P < 0.001). More lesions received TLR at angio- CAC score >245 had an 8.46-fold increased risk in ISR as graphic follow-up in the group with a CAC score >245 compared with those with a CAC score ≤245 after adjust- than those in the group with a CAC score ≤245 (26.5 vs. ment [26.5 vs. 4.5%; adjusted odds ratio (OR), 8.46; 95% 4.5%; P < 0.001). Other demographic, clinical and proce- CI, 2.23–32.13; P = 0.002). dural parameters were comparable between lesions with a CAC score ≤245 and >245 (Supplementary Table S1, In the NCCT/5  mm group, the ROC curve analysis and S2, Supplemental digital content 1, http://links.lww. demonstrated that the lesion CAC score distinguishes com/MCA/A484). In the univariable and multivariable between ISR and non-ISR (area under the curve, 0.704; logistic regression analyses, the CAC score was signifi- 95% CI, 0.549–0.860; P = 0.010; Fig.  5b). The lesion cantly associated with ISR (all P < 0.01; Table 4). A CAC CAC score >209 was identified as the optimal cutoff CAC score for ISR after DES implantation Zheng et al. 289 Fig. 2 Correlations between the coronary artery calcium (CAC) score and in-stent diameter stenosis (a), proximal-edge diameter stenosis (b), distal-edge diameter stenosis (c), in-stent late lumen loss (d), proximal-edge late lumen loss (e), or distal-edge late lumen loss (f) assessed at the angiographic follow-up in all lesions. value providing the greatest sum of sensitivity (46.7%; lesions with a CAC score >209, 7 (41.2%) had ISR, and 95% CI, 21.3–73.4%) and specificity (91.9%; 95% CI, in the 121 lesions with a CAC score ≤209, 8 (6.6%) had 85.6–96.0%). Lesions with a CAC score >209 had higher ISR. The risk of ISR was significantly higher in lesions residual diameter stenosis after the procedure and with a CAC score >209 than in those with a CAC score in-stent minimal lumen diameter, in-stent stenosis and ≤209 (P < 0.001). More lesions received TLR at angio- in-stent late lumen loss at angiographic follow-up in graphic follow-up in the group with a CAC score >209 comparison with those with a CAC score ≤209. In the 17 than those in the group with a CAC score ≤209 (41.2 vs. 290 Coronary Artery Disease 2022, Vol 33 No 4 Fig. 3. 6.6%; P < 0.001). Other demographic, clinical and proce- dural parameters were comparable between lesions with CAC score ≤209 and >209 (Supplementary Table S3 and S4, Supplemental digital content 1, http://links.lww.com/ MCA/A484). In the univariable and multivariable logis- tic regression analyses, the CAC score was significantly associated with ISR (all P < 0.05; Table  4). CAC score >209 in lesions in the NCCT/5 mm group was identified to be independently associated with a higher risk in ISR at the angiographic follow-up. Lesions with a CAC score >209 had a 21.89-fold increased risk in ISR in compar- ison with those with CAC score ≤209 after adjustment (41.2 vs. 6.6%; adjusted OR, 21.89; 95% CI, 4.19–114.35; P < 0.001). Discussion In this study, we demonstrated that the CAC score was significantly associated with increased risk in ISR, irre- spectively of clinical or procedural characteristics. In the CCTA/2.5  mm group, a lesion CAC score >245 was significantly associated with an 8.46-fold increase in ISR. Similarly, in the NCCT/5 mm group, a lesion CAC score >209 was significantly associated with a 21.89-fold increase in ISR. ISR was recognized as a clinically important vessel-ori- ented complication, which may lead to recurrent angina or even myocardial infarction [2,3]. Thanks to the evolu- tion of the coronary stent (e.g. from bare-metal stent to DES, and from the first-generation DES to second-gen- eration DES) and improvement of the stent deploy- ment technique (to achieve no residual narrowing, no presence of dissection and complete stent expansion and apposition), the burden of ISR had been reduced dramatically [1]. However, approximately 5–10% of Correlations between in-stent diameter stenosis and the coronary patients receiving stent implantation may still experi- artery calcium (CAC) score assessed by ECG-gated coronary computed tomography angiography with 2.5-mm detector row width ence ISR [14–16]. Intravascular imaging studies have (CCTA/2.5 mm) and nongated noncontrast chest computed tomogra- demonstrated that stent under-expansion was observed phy with 5-mm detector row width (NCCT/5 mm). in about half of ISR lesions [17]. It is thus essential for interventionists to identify lesions with a higher risk in stent under-expansion and then to optimize interven- tional strategy for eliminating the occurrence of ISR. Table 3. In-stent diameter stenosis and late lumen loss assessed at the angiographic follow-up in lesions with a coronary artery calcium score of 0, 1–25, 26–87, 88–220 and >220 in the ECG-gated coronary computed tomography angiography with 2.5-mm detector row width group and 0, 1–22, 23–67, 68–192, and >192 in the nongated noncontrast chest computed tomography with 5-mm detector row width group CAC score 0 (n = 25) 1–25 (n = 36) 26–87 (n = 36) 88–220 (n = 36) >220 (n = 35) P value a b b CCTA/2.5 mm Diameter stenosis 10.9 ± 5.8 16.8 ± 17 .3 23.1 ± 16.7 28.4 ± 6.5 42.1 ± 17 .3 <0.001 b b b Late lumen loss 0.2 ± 0.1 0.4 ± 0.4 0.6 ± 0.4 0.7 ± 0.3 1.0 ± 0.5 <0.001 CAC score 0 (n = 51) 1–22 (n = 21) 23–67 (n = 22) 68–192 (n = 22) >192 (n = 22) P value c a b NCCT/5 mm Diameter stenosis 13.3 ± 14.4 12.2 ± 6.3 23.4 ± 23.1 26.5 ± 9.2 44.6 ± 17 .2 <0.001 c a b Late lumen loss 0.3 ± 0.5 0.2 ± 0.2 0.6 ± 0.6 0.7 ± 0.2 1.1 ± 0.5 <0.001 Values are mean ± SD or n (%). P values were calculated using one-way ANOVA followed by Dunnett’s tests using the group with CAC score = 0 as the reference group. ANOVA, analysis of variance; CAC, coronary artery calcium; CCTA, coronary computed tomographic angiography; NCCT, noncontrast chest computed tomography. P<0.01. P<0.001. P<0.05. CAC score for ISR after DES implantation Zheng et al. 291 Fig. 4. In-stent diameter stenosis and late lumen loss assessed at the angiographic follow-up in the ECG-gated coronary computed tomography angi- ography with 2.5-mm detector row width (CCTA/2.5 mm) group (a and c) and nongated noncontrast chest computed tomography with 5-mm detector row width (NCCT/5 mm) group (b and d), stratified by the coronary artery calcium (CAC) score. However, a clinically useful tool for preoperative assess- clinical practice. But this assessment is qualitative and ment is lacking. subjective, limiting its standardization and extrapolation. Intracoronary imaging modalities, including IVUS and CAC has been well recognized as an important contribu- OCT, could detect the CAC and provide detailed infor- tor of stent underexpansion. Previous studies have shown mation, but the devices may be hard to cross some lesions a higher risk in ISR in calcified lesions. In a subgroup with severe stenosis or calcium. As compared with angi- analysis of the Cypher Post-Marketing Surveillance ographically visual evaluation and intracoronary imaging Registry study, a significantly higher rate of restenosis modalities, a CT scan is a quantitative, objective and was observed in calcified lesions than that in noncalcified noninvasive approach to detect CAC. Also, it can pro- lesions (39.5 vs. 17.0%; P = 0.029) [18]. Angiographically vide additional information for optimizing pretreatment visual evaluation of CAC is commonly used in routine 292 Coronary Artery Disease 2022, Vol 33 No 4 Fig. 5. identifying lesions with high ISR risk is warranted for further validation. Compared with CCTA, NCCT is more widely used in routine clinical practice, with a simpler procedure and lower cost. The usefulness of NCCT to evaluate the severity of CAC has been explored in previous studies. In a meta-analysis of 661 patients, the correlation coefficient for the agreement of CAC scoring between nongated and ECG-gated CT examinations was 0.94 (95% CI, 0.89– 0.97) [19]. However, its association between CAC sever- ity and ISR has not been compared with CCTA. In our study, we found that a CAC score >245 in the CCTA/2.5 group and a CAC score >209 in the NCCT/5 mm group were both independently associated with a higher risk in ISR, which suggests that NCCT scan has the potential for clinical utility in CAC assessment for ISR prediction in comparison with CCTA scan. Further, it is interest- ing to observe that in this study, the median value of the CAC score in the NCCT/5  mm group was lower than that in the CCTA/2.5 mm group (17 vs. 56.5; P < 0.001). Similarly, in a previous study, the false-negative NCCT for CAC was 8.8% when noted on the ECG-gated scans and 19.1% of high CAC scores were underestimated [19]. It might be explained by the lower radiation dose and wider detector slice in NCCT/5  mm as compared with CCTA/2.5  mm. Thus, a single cutoff value of the CAC score might be not useful for different types of CT scans and different slice thickness. In this study, we determined the individual cutoff value for each of the two CT scan types separately. In both types of CT scans, lesions with a CAC score higher than the cutoff value had significantly increased risk in ISR, and more importantly, more events on TLRs. This suggests that although the absolute val- ues of the CAC score are different, CAC scoring by the Receiver-operating characteristic curve for the coronary artery calcium (CAC) score assessed by ECG-gated coronary computed tomog- NCCT/5 mm scan might have a similar prognostic value raphy angiography with 2.5-mm detector row width (CCTA/2.5 mm) as compared with CCTA, and thus, might be as clinically (a) or nongated noncontrast chest computed tomography with 5-mm detector row width (NCCT/5 mm) (b) to distinguish between lesions useful as CCTA in predicting ISR. The utilities of CAC with and without in-stent restenosis. The optimal cutoff value for assessment by the NCCT/5 mm scan and CCTA/2.5 mm in-stent restenosis is CAC score > 245 (sensitivity: 60.0%; speci- scan are required for further validation. ficity: 83.7%; area under the curve: 0.744; 95% CI, 0.602–0.886; P = 0.002) for ECG-gated CCTA/2.5 mm and > 209 for NCCT/5 mm Previous studies have described multiple contributors (sensitivity: 46.7%; specificity: 91.9%; area under the curve: 0.704; 95% CI, 0.549–0.860; P = 0.010). of ISR, including patient characteristics (e.g. age, female sex, diabetes, multivessel coronary artery disease and genetic variation), lesion characteristics (e.g. prior ISR, strategy for target lesions even before interventional pro- bypass graft, chronic total occlusion, small vessel lesion, cedure. However, the quantitative analyses on the asso- calcified lesion and ostial lesion) and procedural charac- teristics (e.g. type of DES and postprocedural minimal ciation between the magnitude of CT-detected CAC and ISR risk were less investigated. In a study of 69 lesions, lumen diameter) [3,20]. Among these contributors, most Tanabe et al. [10] found higher preprocedural Agatston are unlikely to be modified. In addition, although the calcium scores in lesions with ISR than those without selection of a newer generation of DES and the opti- mization of postprocedural minimal lumen diameter to [(629 ± 718) vs. (153 ± 245); P = 0.08]. In this study, we found that a CAC score >245 in the CCTA/2.5 mm group obtain optimal acute angiographic results could improve or a CAC score >209 in the NCCT/5 mm group was sig- long-term outcomes, these approaches are required for nificantly associated with increased risk in ISR, irrespec- all target lesions. Unlike other contributors, CAC could be identified and quantified before the procedure and tively of clinical or procedural characteristics. Our study provided a clinically feasible tool of preprocedural assess- be theoretically ‘modifiable’ for better stent deployment ment of CAC for predicting long-term ISR. Its utility in and expansion during the procedure with the use of more CAC score for ISR after DES implantation Zheng et al. 293 Table 4. Univariable and multivariable logistic regression analyses for in-stent restenosis assessed at the angiographic follow-up in the ECG-gated coronary computed tomography angiography with 2.5-mm detector row width group and nongated noncontrast chest com- puted tomography with 5-mm detector row width group. Univariable model Multivariable model OR (95% CI) P value OR (95% CI) P value CCTA/2.5 mm group CAC score >245 7.68 (2.51, 23.50) <0.001 8.46 (2.23, 32.13) 0.002 Age >65 years 0.89 (0.31, 2.58) 0.83 1.21 (0.35, 4.12) 0.77 Male sex 1.79 (0.38, 8.32) 0.46 1.41 (0.20, 9.91) 0.73 Hyperlipidaemia 5.47 (0.70, 42.90) 0.11 5.95 (0.70, 50.78) 0.10 Smoking 1.01 (0.32, 3.16) 0.99 0.61 (0.14, 2.73) 0.52 Stent diameter 1.04 (0.29, 3.68) 0.95 0.67 (0.12, 3.71) 0.65 Stent length 1.04 (0.96, 1.12) 0.36 1.04 (0.95, 1.13) 0.44 NCCT/5 mm group CAC score >209 9.89 (2.97, 32.92) <0.001 21.89 (4.19, 114.35) <0.001 Age >65 years 1.38 (0.46, 4.12) 0.56 0.63 (0.14, 2.74) 0.54 Male sex 1.23 (0.37, 4.11) 0.74 3.63 (0.52, 25.46) 0.20 Hyperlipidaemia 5.13 (0.65, 40.58) 0.12 9.74 (0.99, 95.99) 0.051 Smoking 0.78 (0.27, 2.30) 0.66 0.31 (0.05, 1.72) 0.18 Stent diameter 0.60 (0.14, 2.52) 0.49 0.32 (0.05, 2.01) 0.23 Stent length 1.08 (0.99, 1.18) 0.095 1.07 (0.97, 1.19) 0.19 CAC, coronary artery calcium; CCTA, coronary computed tomographic angiography; CI, confidence interval; NCCT, non-contrast chest computed tomography; OR, odds ratio. aggressive interventional approaches, such as cutting This work was supported by the National Natural Science Foundation of China (81830010, 81770428); ballooning [21], rotational atherectomy [21,22], orbital atherectomy [23], excimer laser coronary atherectomy Shanghai Science and Technology Committee [24] and coronary intravascular lithotripsy [25]. These (18411950400); Emerging and Advanced Technology approaches could be planned even before conducting Programs of Hospital Development Center of Shanghai (SHDC12018129); and Shanghai Sailing Program the invasive procedure. Our study provided a clinically useful tool of preprocedural assessment on CAC severity (20YF1444200, 19YF1444600). for tailoring interventional strategy. Conflicts of interest There are some limitations in this study. First, as a ret- There are no conflicts of interest. rospective study, there is selection bias. For example, there is a selected group of patients who underwent References coronary CT. Second, the sample size of this study is 1 Torrado J, Buckley L, Durán A, Trujillo P, Toldo S, Valle Raleigh J, et al. Restenosis, stent thrombosis, and bleeding complications: navigating limited. However, the findings were statistically sig- between scylla and charybdis. J Am Coll Cardiol 2018; 71:1676–1695. nificant and consistent among different subgroup anal- 2 Moussa ID, Mohananey D, Saucedo J, Stone GW, Yeh RW, Kennedy KF, yses. Larger-scale studies are warranted for further et al. Trends and outcomes of restenosis after coronary stent implantation in the United States. J Am Coll Cardiol 2020; 76:1521–1531. confirmation. 3 Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol 2010; In conclusion, our study found that either a CAC 56:1897–1907. score >245 in CCTA/2.5  mm or a CAC score >209 in 4 Henneke KH, Regar E, König A, Werner F, Klauss V, Metz J, et al. Impact NCCT/5  mm was independently associated with a of target lesion calcification on coronary stent expansion after rotational atherectomy. Am Heart J 1999; 137:93–99. higher risk in ISR. Further investigations are warranted 5 Fujino A, Mintz GS, Matsumura M, Lee T, Kim SY, Hoshino M, et al. A new to prospectively validate these findings and test the clin- optical coherence tomography-based calcium scoring system to predict ical usefulness of the CAC score assessed by CCTA or stent underexpansion. EuroIntervention 2018; 13:e2182–e2189. 6 Wang X, Matsumura M, Mintz GS, Lee T, Zhang W, Cao Y, et al. In vivo NCCT in optimizing interventional strategy for severely calcium detection by comparing optical coherence tomography, intra- calcified lesions. vascular ultrasound, and angiography. JACC Cardiovasc Imaging 2017; 10:869–879. 7 Maejima N, Hibi K, Saka K, Akiyama E, Konishi M, Endo M, et al. Acknowledgements Relationship between thickness of calcium on optical coherence tomogra- The authors thank Dr. Weituo Zhang from the School phy and crack formation after balloon dilatation in calcified plaque requiring of Medicine, Shanghai Jiao Tong University, Shanghai, rotational atherectomy. Circ J 2016; 80:1413–1419. 8 Kubo T, Shimamura K, Ino Y, Yamaguchi T, Matsuo Y, Shiono Y, et al. China for the statistical consultation, Dr. Yifeng Jiang from Superficial calcium fracture after PCI as assessed by OCT. JACC the Department of Radiology, Shanghai Chest Hospital, Cardiovasc Imaging 2015; 8:1228–1229. Shanghai Jiao Tong University, Shanghai, China, for tech- 9 Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed nical assistance with CT images and Mr. Hao Zhang from tomography. J Am Coll Cardiol 1990; 15:827–832. Catheter Laboratory, Department of Cardiology, Shanghai 10 Tanabe K, Kishi S, Aoki J, Tanimoto S, Onuma Y, Yachi S, et al. Impact of Chest Hospital, Shanghai Jiao Tong University, Shanghai, coronary calcium on outcome following sirolimus-eluting stent implantation. Am J Cardiol 2011; 108:514–517. China, for technical assistance with angiographic images. 294 Coronary Artery Disease 2022, Vol 33 No 4 18 Fujimoto H, Nakamura M, Yokoi H. Impact of calcification on the long-term 11 Sekimoto T, Akutsu Y, Hamazaki Y, Sakai K, Kosaki R, Yokota H, et al. Regional calcified plaque score evaluated by multidetector computed outcomes of sirolimus-eluting stent implantation: subanalysis of the Cypher tomography for predicting the addition of rotational atherectomy during Post-Marketing Surveillance Registry. Circ J 2012; 76:57–64. percutaneous coronary intervention. J Cardiovasc Comput Tomogr 2016; 19 Xie X, Zhao Y, de Bock GH, de Jong PA, Mali WP, Oudkerk M, Vliegenthart R. Validation and prognosis of coronary artery calcium scoring in nontrig- 10:221–228. 12 Shin JM, Kim TH, Kim JY, Park CH. Coronary artery calcium scoring on non- gered thoracic computed tomography: systematic review and meta-analysis. gated, non-contrast chest computed tomography (CT) using wide-detector, Circ Cardiovasc Imaging 2013; 6:514–521. high-pitch and fast gantry rotation: comparison with dedicated calcium scor- 20 Jørgensen E, Kelbaek H, Helqvist S, Jensen GV, Saunamäki K, Kastrup J, et al. Predictors of coronary in-stent restenosis: importance of angiotensin-con- ing CT. J Thorac Dis 2020; 12:5783–5793. 13 Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, et al. verting enzyme gene polymorphism and treatment with angiotensin-convert- Angiographic patterns of in-stent restenosis: classification and implications ing enzyme inhibitors. J Am Coll Cardiol 2001; 38:1434–1439. for long-term outcome. Circulation 1999; 100:1872–1878. 21 Amemiya K, Yamamoto MH, Maehara A, Oyama Y, Igawa W, Ono M, et al. Effect of cutting balloon after rotational atherectomy in severely calcified cor- 14 Windecker S, Serruys PW, Wandel S, Buszman P, Trznadel S, Linke A, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting onary artery lesions as assessed by optical coherence tomography. Catheter stent with durable polymer for coronary revascularisation (LEADERS): a ran- Cardiovasc Interv 2019; 94:936–944. domised non-inferiority trial. Lancet 2008; 372:1163–1173. 22 Abdel-Wahab M, Toelg R, Byrne RA, Geist V, El-Mawardy M, Allali A, et al. High-speed rotational atherectomy versus modified balloons prior to 15 Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, et al.; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients drug-eluting stent implantation in severely calcified coronary lesions. Circ with coronary artery disease. N Engl J Med 2004; 350:221–231. Cardiovasc Interv 2018; 11:e007415. 16 Morice MC, Colombo A, Meier B, Serruys P, Tamburino C, Guagliumi G, et 23 Redfors B, Sharma SK, Saito S, Kini AS, Lee AC, Moses JW, et al. Novel micro crown orbital atherectomy for severe lesion calcification: Coronary Orbital al.; REALITY Trial Investigators. Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial. Atherectomy System Study (COAST). Circ Cardiovasc Interv 2020; 13:e008993. JAMA 2006; 295:895–904. 24 Ojeda S, Azzalini L, Suárez de Lezo J, Johal GS, González R, Barman N, et 17 Jensen LO, Vikman S, Antonsen L, Kosonen P, Niemelä M, Christiansen al. Excimer laser coronary atherectomy for uncrossable coronary lesions. A multicenter registry. Catheter Cardiovasc Interv 2021; 98:1241–1249. EH, et al. Intravascular ultrasound assessment of minimum lumen area and intimal hyperplasia in in-stent restenosis after drug-eluting or bare-metal 25 Hill JM, Kereiakes DJ, Shlofmitz RA, Klein AJ, Riley RF, Price MJ, et al.; Disrupt stent implantation. The Nordic Intravascular Ultrasound Study (NIVUS). CAD III Investigators. Intravascular lithotripsy for treatment of severely calci- Cardiovasc Revasc Med 2017; 18:577–582. fied coronary artery disease. J Am Coll Cardiol 2020; 76 :2635–2646. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Anti-Cancer Drugs Wolters Kluwer Health

Association between coronary artery calcium score and in-stent restenosis after drug-eluting stent implantation

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284 Original article Association between coronary artery calcium score and in-stent restenosis after drug-eluting stent implantation Xiaowen Zheng*, Ke Xu*, Xiaoxiao Yang, Wentao Yang, Weifeng Zhang, Yue Jiang, Yipeng Zhang, Xingbiao Qiu, Hongyu Shi, Lisheng Jiang, Linghong Shen, and Ben He Background Coronary artery calcium (CAC) is a specificity, 91.9%; area under the curve, 0.704; P < 0.001). modifiable contributor of in-stent restenosis (ISR), but Multivariable logistic regression models indicated a quantitative analyses using a noninvasive approach are CAC score >245 in CCTA/2.5 mm group and >209 in limited. We aimed to investigate the associations between NCCT/5 mm group independently associated with an 8.46- CAC score derived from ECG-gated coronary computed and 21.89-fold increase in ISR, respectively (all P < 0.01). tomography angiography (CCTA) or non-gated non- Conclusions Either a CAC score >245 in CCTA/2.5 mm contrast chest computed tomography (NCCT) and ISR. or >209 in NCCT/5 mm was significantly associated Methods We included 368 lesions in 194 patients with increased risk in ISR. Coron Artery Dis 33: 284–294 with coronary drug-eluting stent implantations in final Copyright © 2022 The Author(s). Published by Wolters analyses. CAC was quantified using the Agatston score. Kluwer Health, Inc. Primary endpoint was ISR, defined as lumen diameter Coronary Artery Disease 2022, 33:284–294 stenosis over 50% at the stent segment or its proximal or Keywords: coronary artery calcium, coronary computed tomography distal edges (5-mm segments adjacent to the stent), at angiography, in-stent restenosis, nongated noncontrast chest computed angiographic follow-up. tomography, percutaneous coronary intervention Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong Results The CAC scores in either CCTA/2.5 mm group University, Shanghai, China (r = 0.7702; P < 0.0001) or NCCT/5 mm group (r = 0.7105; P < 0.0001) were both correlated with in-stent diameter Correspondence to Dr. Linghong Shen, MD, PhD, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai stenosis. The receiver-operating characteristic curve Road, Shanghai, 200030, China analysis identified a CAC score >245 in CCTA/2.5 mm Tel: +86 21 22200000; e-mail: rjshenlinghong@126.com. group as the optimal ISR cutoff (sensitivity, 60.0%; *Dr. Xiaowen Zheng and Dr. Ke Xu are considered as co-first authors. specificity, 83.7%; area under the curve, 0.744; P < 0.001), Received 15 June 2021 Accepted 12 December 2021 and >209 in NCCT/5 mm group (sensitivity, 46.7%; Introduction According to the results from studies of intravascular In-stent restenosis (ISR) is well recognized as a clinically imaging, stent expansion is mainly associated with the significant complication after coronary stent implantation, angle, length and thickness of calcium deposition. Using observed in 20–30% of patients undergoing bare-metal intravascular ultrasound (IVUS), stent expansion was stent implantation and 5–15% undergoing drug-eluting found to be inversely correlated with the arc of calcium stent (DES) implantation [1,2]. It may be due to bio- [4]. An optical coherence tomography (OCT)-based cal- logic, mechanic or technical factors [3]. Of these, stent cium scoring system further demonstrated that lesions under-expansion plays an important role and coronary with a maximum angle greater than 180°, maximum artery calcium (CAC) has been recognized as a major thickness more than 0.5 mm and length more than 5 mm determinant of stent underexpansion during the percu- would be at risk of stent underexpansion [5]. Although taneous coronary intervention (PCI). Thus, an accurate it was generally agreed that coronary angiography was evaluation of CAC is of clinical significance in planning less sensitive to detect CAC compared to intravascular a PCI strategy. imaging, Wang et al., [6] recently reported that angio- graphically invisible calcium (only detectable by IVUS or OCT) did not appear to inhibit stent expansion and angi- Supplemental Digital Content is available for this article. Direct URL citations ographically visible calcium seemed to be a good marker appear in the printed text and are provided in the HTML and PDF versions of this for predicting stent underexpansion [6]. It might be article on the journal’s website, www.coronary-artery.com. because some of the angiographically invisible calcium This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- were thinner (<0.50  mm) in thickness, which is associ- NC-ND), where it is permissible to download and share the work provided it is ated with a greater stent expansion because of calcium properly cited. The work cannot be changed in any way or used commercially fracture during PCI [7,8]. Therefore, the evaluation of without permission from the journal. 0954-6928 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/MCA.0000000000001124 CAC score for ISR after DES implantation Zheng et al. 285 calcium density and total volume is imperative for pre- coronary angiography (QCA). We assumed that ISR in dicting stent expansion. the vessel with reference diameter below 2.5  mm may be mainly caused by a small in-stent lumen diameter but Computed tomography (CT) is the only noninvasive not CAC. modality with high sensitivity and specificity for cal- cium detection. Usually, the severity of CAC assessed Study endpoints by CT images is quantified with a method introduced by The primary endpoint of this study was ISR at angio- Agatston et al., [9] called the Agatston score. It takes into graphic follow-up, defined as lumen diameter stenosis account both the area and peak density of calcified lesions. over 50% at the stent segment or its proximal or distal Previous studies have suggested that the Agatston score edges (5-mm segments adjacent to the stent) [13]. We correlates to late lumen loss [10] and might be helpful in assessed lumen diameter stenosis and late lumen loss by determining the treatment strategy for complex coronary QCA, that is, diameter stenosis = (reference vessel diam- artery lesions with severe calcification [11]. However, the eter − minimal lumen diameter)/reference vessel diame- exact relationship between the calcium score and ISR is ter × 100%), and late lumen loss = postprocedural minimal not well understood. lumen diameter − minimal lumen diameter at follow-up. Target lesion revascularization (TLR) was also recorded Traditionally, Agatston-score assessment is based on ECG-gated coronary CT angiography (CCTA) [9]. with medical chart review. However, nongated noncontrast chest CT (NCCT) is more technically simple and widely used in routine prac- Quantitative coronary angiography analysis tice compared with CCTA. Previous studies have illus- QCA was performed following the standard proce- trated a high correlation between NCCT and CCTA for dure of analysis using a validated software (QAngio CAC quantification [12]. However, the utility of CAC XA 7.3, Medis Medical Imaging Systems, Leiden, the quantification using NCCT for predicting ISR after cor - Netherlands). QCA was analyzed by two independent, onary stent implantation has not been well described. well-trained technicians who had performed QCA in at Moreover, a clinically useful cutoff value of CAC severity least 50 patients, who were blinded with data on CAC for optimizing interventional strategy to reduce ISR risk score. Case examples were present in Supplementary has not been well determined. Figure S1–S6, Supplemental digital content 1, http://links. lww.com/MCA/A484. Accordingly, we performed this study to explore the asso- ciations between CCTA- or NCCT-derived CAC score Computed tomography and coronary artery calcium and ISR. quantification Images of CCTA or NCCT were acquired using sin- Methods gle-source ≥64-row CT scanners. Using reproducible land- Study design marks such as the ostium of main vessel and side branches, This single-center, retrospective study was conducted in the target segment undergoing PCI was determined on Shanghai Chest Hospital, Shanghai Jiao Tong University, images of CCTA or NCCT with the use of angiographic following the principles of the Declaration of Helsinki images as a reference. Scans were interpreted by two and local regulations. This study was approved by the investigators independently, who were blinded with data ethics committee of Shanghai Chest Hospital, Shanghai on QCA analyses. CAC was quantified using the Agatston Jiao Tong University. Written informed consents were method [9] with a commercially available software (OsiriX, waived. Pixmeo SARL, Bernex, Switzerland). Case examples were present in Supplementary Figure S1–S6, Supplemental Study population digital content 1, http://links.lww.com/MCA/A484. We retrospectively screened patients (≥18 years) under- going DES implantation for de novo coronary lesions in the Department of Cardiology, Shanghai Chest Hospital, Statistical analyses Shanghai Jiao Tong University from January 2010 to Descriptive statistics are presented as mean ± SD, median January 2020. We enrolled patients who had documented (interquartile range) or number (percentage) as appropri- coronary angiographic images at both index procedure ate. Data were presented on a per-patient basis for clini- and follow-up after 6–18 months and received a CT (i.e. cal characteristics and per-vessel basis for the remaining NCCT or CCTA) scan within 3 months before index pro- analyses. We compared target lesion and procedural char- cedure. Exclusion criteria were ST-segment-elevation acteristics and angiographic parameters before and after myocardial infarction, prior coronary artery bypass graft- the index procedure and at the angiographic follow-up ing, chronic renal failure, hemodialysis, or metal implants between groups with the use of unpaired Student’s t-test, affecting CAC quantification. Angiographic exclusion cri- Mann–Whitney U tests or chi-square tests as appropri- teria were stent fracture or reference vessel diameter of ate. The lesion CAC score was correlated with in-stent, the target lesion below 2.5 mm assessed by quantitative proximal-edge and distal-edge diameter stenosis and 286 Coronary Artery Disease 2022, Vol 33 No 4 lumen late loss. CAC score in lesions with ISR was com- follow-up. Age greater than 65 years, male sex, hyperlipi- pared with that in the lesion with no ISR with the use of demia, smoking, stent diameter and stent length were Mann–Whitney U tests. Considering that (1) CCTA with included in multivariable analyses. 2.5-mm detector row width (CCTA/2.5 mm) and NCCT All analyses were conducted with the STATA software with 5-mm detector row width (NCCT/5  mm) account version 14.0 (Stata Corp, College Station, Texas, USA) for the highest percentage of included lesions and and GraphPad Prism version 5.0.1 (GraphPad Software, patients as shown in Table  1 (indicating that these two San Diego, California, USA). A two-sided P value of types of CT scan may be the mostly used in clinical prac- <0.05 was considered statistically significant. tice) and (2) we recognized that the detector row width of CT scan may affect the cutoff value, we chose to perform Results subgroup analyses in lesions receiving CCTA/2.5  mm Baseline clinical, lesion and procedural characteristics (168 lesions in 90 patients) and NCCT/5 mm scans (138 We screened 5158 patients receiving DES implantation. lesions in 71 patients) and generated specific cutoff Finally, 368 lesions in 194 patients which met the inclu- values for each type of the CT scan. We set the lesions sion criteria and had none of the exclusion criteria were with CAC score = 0 as the reference group, and divided included in the analyses (Fig.  1). The demographic and the lesions with CAC score > 0 into quartiles. We com- clinical characteristics of the patients are summarized in pared the in-stent diameter stenosis and late lumen loss Table  1. The mean age of patients was 67.2 ± 8.5 years, among groups with different CAC scores with the use and 70.1% were male. Ninety-five patients received the of one-way analysis of variance followed by Dunnett’s NCCT scan. Of these, 71 had NCCT with 5-mm detec- tests using the group with CAC score = 0 as the reference tor row width and 24 with ≤3-mm detector row width. group. Divided by the cutoff point of the CAC score, Ninety-nine patients received the CCTA scan. Of these, target lesion and procedural characteristics and angio- 90 had CCTA with 2.5-mm detector row width and 9 with graphic parameters before and after the index proce- ≤1.5-mm detector row width. The demographic and clin- dure and at the angiographic follow-up were compared ical characteristics of the patients in the CCTA/2.5  mm as described above in the CCTA/2.5  mm group or the group and NCCT/5  mm group are summarized in NCCT/5  mm group. A receiver-operating characteristic Supplementary Table S1, Supplemental digital content (ROC) curve analysis was used to determine the ability 1, http://links.lww.com/MCA/A484. The percentage of of the lesion CAC score to distinguish between lesions patients with the acute coronary syndrome (i.e. unstable with and without ISR at angiographic follow-up and angina or non-ST-segment elevation myocardial infarc- identify the optimal cutoff point of the lesion CAC score tion) in the NCCT/5 mm group was higher than that in that provided the greatest sum of sensitivity and spec- the CCTA/2.5 mm group. Other baseline characteristics ificity in the CCTA/2.5  mm group or the NCCT/5  mm were comparable. The baseline lesion and procedural group, respectively. Univariable and multivariable logis- characteristics are presented in Table  2. Half (49.5%) of tic regression models were performed to determine the target lesions were located at the left anterior descending association between CAC score and ISR at angiographic artery, 20.6% at the left circumflex artery and 29.9% at the right coronary artery. The median CAC score was 32, and the minimal and maximal scores were 0 and 1085, Table 1. Baseline clinical characteristics of all patients included in analyses (n = 194). respectively. Two patients received advanced techniques for severe CAC. One with a CAC score of 307 received Characteristics cutting balloon inflation, and the other with a CAC score Age, years 67 .2 ± 8.5 of 272 received rotational atherectomy. Most lesions Male sex 136 (70.1) Diagnosis (78.3%) were treated by implanting a sirolimus-elut- Stable angina or silent ischemia 104 (53.6) ing stent. The mean stent diameter and length were Unstable angina 53 (27.3) 3.0 ± 0.4  mm and 27.5 ± 7.3  mm, respectively. T able  2 Non-ST-segment elevation myocardial infarction 37 (19.1) Hypertension 142 (73.2) presents the angiographic characteristics of target lesions Diabetes mellitus 77 (39.7) at index procedure and follow-up. The mean duration Hyperlipidaemia 138 (71.1) Smoking 111 (57.2) between the index procedure and angiographic follow-up Multivessel disease was 12.8 ± 5.4 months. Preprocedural diameter stenosis of 1 vessel 61 (31.4) 2 vessels 70 (35.6) the target lesion was (72.8 ± 14.5)%, and in-stent diam- 3 vessels 63 (33.0) eter stenosis was (9.9 ± 4.2)% after the procedure and Type of CT/detector row width (22.8 ± 17.4)% at angiographic follow-up. Thirty-two CCTA/≤1.5 mm 9 (4.6) CCTA/2.5 mm 90 (46.4) (8.7%) lesions received TLR at the angiographic fol- NCCT/≤3 mm 24 (12.4) low-up. The procedural and angiographic characteristics NCCT/5 mm 71 (36.6) of the CCTA/2.5-mm and NCCT/5-mm groups were Values are mean ± SD or n (%). present in Supplementary Table S2–S5, Supplemental CCTA, coronary computed tomography angiography; CT, computed tomography; digital content 1, http://links.lww.com/MCA/A484. NCCT, noncontrast chest computed tomography. CAC score for ISR after DES implantation Zheng et al. 287 Fig. 1. Study flow diagram. CABG, coronary artery bypass grafting; CAC, coronary artery calcium; CCTA, coronary computed tomographic angiography; DES, drug-eluting stent; NCCT, noncontrast chest computed tomography; PCI, percutaneous coronary intervention; QCA, quantitative coronary angiography; STEMI, ST-segment elevation myocardial infarction. Coronary artery calcium score, diameter stenosis, late Coronary artery calcium score, in-stent diameter lumen loss and in-stent restenosis stenosis and in-stent restenosis in lesions receiving the In Fig. 2, the lesion CAC score was significantly correlated noncontrast chest computed tomography/5 mm scan with in-stent diameter stenosis (Spearman r = 0.7357; In the NCCT/5  mm group, the lesion CAC score was P < 0.0001) but not proximal-edge (Spearman r = 0.0724; significantly correlated with in-stent diameter stenosis P = 0.17) or distal-edge diameter stenosis (Spearman (Spearman r = 0.7105; P < 0.0001; Fig. 3). In-stent diame- r = 0.0762; P = 0.14) assessed at angiographic follow-up. ter stenosis and late lumen loss were significantly higher The lesion CAC score was significantly correlated with in lesions with CAC scores of 23–67, 68–192, or >192 in-stent (Spearman r = 0.7306; P < 0.0001), proximal-edge than those with a CAC score of 0 (all P < 0.05; T able  3; (Spearman r = 0.1931; P = 0.0002) and distal-edge late Fig. 4). Among the 138 lesions in the NCCT/5 mm group, lumen loss (Spearman r = 0.2136; P < 0.0001). Among the 15 (10.9%) had ISR. Lesions with ISR had significantly 368 lesions, 32 (8.7%) had ISR. Lesions with ISR had sig- higher CAC scores than those with no ISR [130 (28, 325) nificantly higher CAC scores than those with no ISR [189 vs. 10 (0, 96); P = 0.0082). (28, 512) vs. 29.5 (0, 131.5); P = 0.0002]. No ISRs were observed in patients who received advanced techniques. Receiver-operating characteristic analyses In the CCTA/2.5  mm group, the ROC curve analysis Coronary artery calcium score, in-stent diameter demonstrated that a lesion CAC score distinguishes stenosis and in-stent restenosis in lesions receiving the between ISR and non-ISR [area under the curve, 0.744; coronary computed tomography angiography/2.5 mm 95% confidence interval (CI), 0.602– 0.886; P = 0.002; scan Fig.  5a]. The lesion CAC score greater than 245 was In the CCTA/2.5  mm group, the lesion CAC score was identified as the optimal cutoff value providing the great- significantly correlated with in-stent diameter stenosis est sum of sensitivity (60.0%; 95% CI, 32.4–83.7%) and (Spearman r = 0.7702; P < 0.0001; Fig. 3). In-stent diame- specificity (83.7%; 95% CI, 76.8– 89.1%). Lesions with a ter stenosis and late lumen loss were significantly higher CAC score greater than 245 had higher residual diam- in lesions with CAC scores of 26–87, 88–220 or >220 than eter stenosis after the procedure and in-stent minimal those with a CAC score of 0 (all P < 0.05; Table 3; Fig. 4). lumen diameter, in-stent diameter stenosis and in-stent Among the 168 lesions in the CCTA/2.5  mm group, late lumen loss at angiographic follow-up as compared 15 (8.9%) had ISR. Lesions with ISR had significantly with those with CAC score ≤245. In the 34 lesions with higher CAC scores than those with no ISR [251 (43, 620) a CAC score greater than 245, 9 (26.5%) had ISR, and vs. 47 (5, 176.5); P = 0.0019). in the 134 lesions with a CAC score ≤245, 6 (4.5%) had 288 Coronary Artery Disease 2022, Vol 33 No 4 Table 2. Baseline lesion, procedural, angiographic characteristics of target lesions at index procedure and follow-up, stratified by coro- nary artery calcium score Overall (n = 368) CAC score = 0 (n = 94) CAC score > 0 (n = 274) P value Baseline lesion and procedural characteristics Location of target lesions 0.010 LAD 182 (49.5) 34 (36.2) 148 (54.0) LCx 76 (20.6) 23 (24.5) 53 (19.3) RCA 110 (29.9) 37 (39.4) 73 (26.6) CAC score 32 (0, 153.8) 0 67 (22, 192.5) <0.001 ACC/AHA classification 0.001 A 29 (7.9) 10 (10.6) 19 (6.9) B 120 (32.6) 43 (45.8) 77 (28.1) C 219 (59.5) 41 (43.6) 178 (65.0) TIMI flow at baseline 0.41 0 25 (6.8) 3 (3.2) 22 (8.0) 1 27 (7.3) 6 (6.4) 21 (7.7) 2 113 (30.7) 30 (31.9) 83 (30.3) 3 203 (55.2) 55 (58.5) 148 (54.0) Stent type 0.24 Sirolimus-eluting stent 288 (78.3) 69 (73.4) 219 (79.9) Zotarolimus-eluting stent 48 (13.0) 13 (13.8) 35 (12.8) Everolimus-eluting stent 32 (8.7) 12 (12.8) 20 (7.3) Stent diameter, mm 3.0 ± 0.4 2.9 ± 0.4 3.0 ± 0.4 0.26 Stent length, mm 27 .5 ± 7 .3 27 .3 ± 7 .5 27 .6 ± 7 .2 0.75 Maximal balloon pressure, atm 18.5 ± 3.8 16.9 ± 3.1 19.1 ± 3.9 <0.0001 Angiographic characteristics of target lesions at index procedure and follow-up Before procedure Minimal lumen diameter, mm 0.8 ± 0.4 0.8 ± 0.4 0.8 ± 0.5 0.22 Reference vessel diameter, mm 2.9 ± 0.4 2.9 ± 0.4 2.9 ± 0.4 0.78 Diameter stenosis, % 72.8 ± 14.5 70.8 ± 13.2 73.4 ± 14.9 0.14 Length of target lesions, mm 22.4 ± 7 .2 21.5 ± 7 .2 22.7 ± 7 .2 0.16 After procedure Minimal lumen diameter, mm Proximal 3.0 ± 0.5 3.0 ± 0.5 3.1 ± 0.6 0.27 In-stent 2.8 ± 0.4 2.8 ± 0.4 2.8 ± 0.4 0.20 Distal 2.5 ± 0.5 2.5 ± 0.5 2.5 ± 0.5 0.58 Residual diameter stenosis, % Proximal 7 .1 ± 7 .4 7 .2 ± 6.7 7 .1 ± 7 .7 0.91 In-stent 9.9 ± 4.2 7 .4 ± 2.4 10.8 ± 4.4 <0.001 Distal 8.7 ± 8.0 9.1 ± 7 .9 8.6 ± 8.0 0.56 Follow-up Minimal lumen diameter, mm Proximal 2.9 ± 1.1 3.1 ± 1.8 2.8 ± 0.7 0.012 In-stent 2.2 ± 0.6 2.6 ± 0.5 2.1 ± 0.6 <0.001 Distal 2.3 ± 0.6 2.4 ± 0.5 2.3 ± 0.6 0.038 Diameter stenosis, % Proximal 10.5 ± 15.5 9.2 ± 15.5 11.0 ± 15.5 0.33 In-stent 22.8 ± 17 .4 12.7 ± 11.3 26.3 ± 17 .8 <0.001 Distal 12.0 ± 13.1 9.7 ± 10.2 12.8 ± 13.8 0.052 Late lumen loss, mm Proximal 0.2 ± 1.0 −0.1 ± 1.8 0.3 ± 0.5 0.001 In-stent 0.5 ± 0.5 0.2 ± 0.4 0.6 ± 0.5 <0.001 Distal 0.2 ± 0.5 0.1 ± 0.4 0.3 ± 0.5 0.060 Target lesion revascularization 32 (8.7) 4 (4.3) 28 (10.2) 0.077 Values are mean ± SD, median (interquartile range), or n (%). CAC score was calculated using the Agatston score. P values were calculated for the comparison between groups with CAC score = 0 and CAC score >0 with the use of unpaired Student t-tests, Mann–Whitney U tests, or chi-square tests as appropriate. ACC/AHA, American College of Cardiology/American Heart Association; CAC, coronary artery calcium; LAD, left anterior descending artery; LCx, left circumflex artery; RCA, right coronary artery; TIMI, Thrombolysis In Myocardial Infarction. ISR. The risk of ISR was significantly higher in lesions score >245 in lesions in the CCTA/2.5  mm group was with a CAC score >245 than in those with a CAC score identified to be independently associated with a higher risk in ISR at the angiographic follow-up. Lesions with a ≤245 (P < 0.001). More lesions received TLR at angio- CAC score >245 had an 8.46-fold increased risk in ISR as graphic follow-up in the group with a CAC score >245 compared with those with a CAC score ≤245 after adjust- than those in the group with a CAC score ≤245 (26.5 vs. ment [26.5 vs. 4.5%; adjusted odds ratio (OR), 8.46; 95% 4.5%; P < 0.001). Other demographic, clinical and proce- CI, 2.23–32.13; P = 0.002). dural parameters were comparable between lesions with a CAC score ≤245 and >245 (Supplementary Table S1, In the NCCT/5  mm group, the ROC curve analysis and S2, Supplemental digital content 1, http://links.lww. demonstrated that the lesion CAC score distinguishes com/MCA/A484). In the univariable and multivariable between ISR and non-ISR (area under the curve, 0.704; logistic regression analyses, the CAC score was signifi- 95% CI, 0.549–0.860; P = 0.010; Fig.  5b). The lesion cantly associated with ISR (all P < 0.01; Table 4). A CAC CAC score >209 was identified as the optimal cutoff CAC score for ISR after DES implantation Zheng et al. 289 Fig. 2 Correlations between the coronary artery calcium (CAC) score and in-stent diameter stenosis (a), proximal-edge diameter stenosis (b), distal-edge diameter stenosis (c), in-stent late lumen loss (d), proximal-edge late lumen loss (e), or distal-edge late lumen loss (f) assessed at the angiographic follow-up in all lesions. value providing the greatest sum of sensitivity (46.7%; lesions with a CAC score >209, 7 (41.2%) had ISR, and 95% CI, 21.3–73.4%) and specificity (91.9%; 95% CI, in the 121 lesions with a CAC score ≤209, 8 (6.6%) had 85.6–96.0%). Lesions with a CAC score >209 had higher ISR. The risk of ISR was significantly higher in lesions residual diameter stenosis after the procedure and with a CAC score >209 than in those with a CAC score in-stent minimal lumen diameter, in-stent stenosis and ≤209 (P < 0.001). More lesions received TLR at angio- in-stent late lumen loss at angiographic follow-up in graphic follow-up in the group with a CAC score >209 comparison with those with a CAC score ≤209. In the 17 than those in the group with a CAC score ≤209 (41.2 vs. 290 Coronary Artery Disease 2022, Vol 33 No 4 Fig. 3. 6.6%; P < 0.001). Other demographic, clinical and proce- dural parameters were comparable between lesions with CAC score ≤209 and >209 (Supplementary Table S3 and S4, Supplemental digital content 1, http://links.lww.com/ MCA/A484). In the univariable and multivariable logis- tic regression analyses, the CAC score was significantly associated with ISR (all P < 0.05; Table  4). CAC score >209 in lesions in the NCCT/5 mm group was identified to be independently associated with a higher risk in ISR at the angiographic follow-up. Lesions with a CAC score >209 had a 21.89-fold increased risk in ISR in compar- ison with those with CAC score ≤209 after adjustment (41.2 vs. 6.6%; adjusted OR, 21.89; 95% CI, 4.19–114.35; P < 0.001). Discussion In this study, we demonstrated that the CAC score was significantly associated with increased risk in ISR, irre- spectively of clinical or procedural characteristics. In the CCTA/2.5  mm group, a lesion CAC score >245 was significantly associated with an 8.46-fold increase in ISR. Similarly, in the NCCT/5 mm group, a lesion CAC score >209 was significantly associated with a 21.89-fold increase in ISR. ISR was recognized as a clinically important vessel-ori- ented complication, which may lead to recurrent angina or even myocardial infarction [2,3]. Thanks to the evolu- tion of the coronary stent (e.g. from bare-metal stent to DES, and from the first-generation DES to second-gen- eration DES) and improvement of the stent deploy- ment technique (to achieve no residual narrowing, no presence of dissection and complete stent expansion and apposition), the burden of ISR had been reduced dramatically [1]. However, approximately 5–10% of Correlations between in-stent diameter stenosis and the coronary patients receiving stent implantation may still experi- artery calcium (CAC) score assessed by ECG-gated coronary computed tomography angiography with 2.5-mm detector row width ence ISR [14–16]. Intravascular imaging studies have (CCTA/2.5 mm) and nongated noncontrast chest computed tomogra- demonstrated that stent under-expansion was observed phy with 5-mm detector row width (NCCT/5 mm). in about half of ISR lesions [17]. It is thus essential for interventionists to identify lesions with a higher risk in stent under-expansion and then to optimize interven- tional strategy for eliminating the occurrence of ISR. Table 3. In-stent diameter stenosis and late lumen loss assessed at the angiographic follow-up in lesions with a coronary artery calcium score of 0, 1–25, 26–87, 88–220 and >220 in the ECG-gated coronary computed tomography angiography with 2.5-mm detector row width group and 0, 1–22, 23–67, 68–192, and >192 in the nongated noncontrast chest computed tomography with 5-mm detector row width group CAC score 0 (n = 25) 1–25 (n = 36) 26–87 (n = 36) 88–220 (n = 36) >220 (n = 35) P value a b b CCTA/2.5 mm Diameter stenosis 10.9 ± 5.8 16.8 ± 17 .3 23.1 ± 16.7 28.4 ± 6.5 42.1 ± 17 .3 <0.001 b b b Late lumen loss 0.2 ± 0.1 0.4 ± 0.4 0.6 ± 0.4 0.7 ± 0.3 1.0 ± 0.5 <0.001 CAC score 0 (n = 51) 1–22 (n = 21) 23–67 (n = 22) 68–192 (n = 22) >192 (n = 22) P value c a b NCCT/5 mm Diameter stenosis 13.3 ± 14.4 12.2 ± 6.3 23.4 ± 23.1 26.5 ± 9.2 44.6 ± 17 .2 <0.001 c a b Late lumen loss 0.3 ± 0.5 0.2 ± 0.2 0.6 ± 0.6 0.7 ± 0.2 1.1 ± 0.5 <0.001 Values are mean ± SD or n (%). P values were calculated using one-way ANOVA followed by Dunnett’s tests using the group with CAC score = 0 as the reference group. ANOVA, analysis of variance; CAC, coronary artery calcium; CCTA, coronary computed tomographic angiography; NCCT, noncontrast chest computed tomography. P<0.01. P<0.001. P<0.05. CAC score for ISR after DES implantation Zheng et al. 291 Fig. 4. In-stent diameter stenosis and late lumen loss assessed at the angiographic follow-up in the ECG-gated coronary computed tomography angi- ography with 2.5-mm detector row width (CCTA/2.5 mm) group (a and c) and nongated noncontrast chest computed tomography with 5-mm detector row width (NCCT/5 mm) group (b and d), stratified by the coronary artery calcium (CAC) score. However, a clinically useful tool for preoperative assess- clinical practice. But this assessment is qualitative and ment is lacking. subjective, limiting its standardization and extrapolation. Intracoronary imaging modalities, including IVUS and CAC has been well recognized as an important contribu- OCT, could detect the CAC and provide detailed infor- tor of stent underexpansion. Previous studies have shown mation, but the devices may be hard to cross some lesions a higher risk in ISR in calcified lesions. In a subgroup with severe stenosis or calcium. As compared with angi- analysis of the Cypher Post-Marketing Surveillance ographically visual evaluation and intracoronary imaging Registry study, a significantly higher rate of restenosis modalities, a CT scan is a quantitative, objective and was observed in calcified lesions than that in noncalcified noninvasive approach to detect CAC. Also, it can pro- lesions (39.5 vs. 17.0%; P = 0.029) [18]. Angiographically vide additional information for optimizing pretreatment visual evaluation of CAC is commonly used in routine 292 Coronary Artery Disease 2022, Vol 33 No 4 Fig. 5. identifying lesions with high ISR risk is warranted for further validation. Compared with CCTA, NCCT is more widely used in routine clinical practice, with a simpler procedure and lower cost. The usefulness of NCCT to evaluate the severity of CAC has been explored in previous studies. In a meta-analysis of 661 patients, the correlation coefficient for the agreement of CAC scoring between nongated and ECG-gated CT examinations was 0.94 (95% CI, 0.89– 0.97) [19]. However, its association between CAC sever- ity and ISR has not been compared with CCTA. In our study, we found that a CAC score >245 in the CCTA/2.5 group and a CAC score >209 in the NCCT/5 mm group were both independently associated with a higher risk in ISR, which suggests that NCCT scan has the potential for clinical utility in CAC assessment for ISR prediction in comparison with CCTA scan. Further, it is interest- ing to observe that in this study, the median value of the CAC score in the NCCT/5  mm group was lower than that in the CCTA/2.5 mm group (17 vs. 56.5; P < 0.001). Similarly, in a previous study, the false-negative NCCT for CAC was 8.8% when noted on the ECG-gated scans and 19.1% of high CAC scores were underestimated [19]. It might be explained by the lower radiation dose and wider detector slice in NCCT/5  mm as compared with CCTA/2.5  mm. Thus, a single cutoff value of the CAC score might be not useful for different types of CT scans and different slice thickness. In this study, we determined the individual cutoff value for each of the two CT scan types separately. In both types of CT scans, lesions with a CAC score higher than the cutoff value had significantly increased risk in ISR, and more importantly, more events on TLRs. This suggests that although the absolute val- ues of the CAC score are different, CAC scoring by the Receiver-operating characteristic curve for the coronary artery calcium (CAC) score assessed by ECG-gated coronary computed tomog- NCCT/5 mm scan might have a similar prognostic value raphy angiography with 2.5-mm detector row width (CCTA/2.5 mm) as compared with CCTA, and thus, might be as clinically (a) or nongated noncontrast chest computed tomography with 5-mm detector row width (NCCT/5 mm) (b) to distinguish between lesions useful as CCTA in predicting ISR. The utilities of CAC with and without in-stent restenosis. The optimal cutoff value for assessment by the NCCT/5 mm scan and CCTA/2.5 mm in-stent restenosis is CAC score > 245 (sensitivity: 60.0%; speci- scan are required for further validation. ficity: 83.7%; area under the curve: 0.744; 95% CI, 0.602–0.886; P = 0.002) for ECG-gated CCTA/2.5 mm and > 209 for NCCT/5 mm Previous studies have described multiple contributors (sensitivity: 46.7%; specificity: 91.9%; area under the curve: 0.704; 95% CI, 0.549–0.860; P = 0.010). of ISR, including patient characteristics (e.g. age, female sex, diabetes, multivessel coronary artery disease and genetic variation), lesion characteristics (e.g. prior ISR, strategy for target lesions even before interventional pro- bypass graft, chronic total occlusion, small vessel lesion, cedure. However, the quantitative analyses on the asso- calcified lesion and ostial lesion) and procedural charac- teristics (e.g. type of DES and postprocedural minimal ciation between the magnitude of CT-detected CAC and ISR risk were less investigated. In a study of 69 lesions, lumen diameter) [3,20]. Among these contributors, most Tanabe et al. [10] found higher preprocedural Agatston are unlikely to be modified. In addition, although the calcium scores in lesions with ISR than those without selection of a newer generation of DES and the opti- mization of postprocedural minimal lumen diameter to [(629 ± 718) vs. (153 ± 245); P = 0.08]. In this study, we found that a CAC score >245 in the CCTA/2.5 mm group obtain optimal acute angiographic results could improve or a CAC score >209 in the NCCT/5 mm group was sig- long-term outcomes, these approaches are required for nificantly associated with increased risk in ISR, irrespec- all target lesions. Unlike other contributors, CAC could be identified and quantified before the procedure and tively of clinical or procedural characteristics. Our study provided a clinically feasible tool of preprocedural assess- be theoretically ‘modifiable’ for better stent deployment ment of CAC for predicting long-term ISR. Its utility in and expansion during the procedure with the use of more CAC score for ISR after DES implantation Zheng et al. 293 Table 4. Univariable and multivariable logistic regression analyses for in-stent restenosis assessed at the angiographic follow-up in the ECG-gated coronary computed tomography angiography with 2.5-mm detector row width group and nongated noncontrast chest com- puted tomography with 5-mm detector row width group. Univariable model Multivariable model OR (95% CI) P value OR (95% CI) P value CCTA/2.5 mm group CAC score >245 7.68 (2.51, 23.50) <0.001 8.46 (2.23, 32.13) 0.002 Age >65 years 0.89 (0.31, 2.58) 0.83 1.21 (0.35, 4.12) 0.77 Male sex 1.79 (0.38, 8.32) 0.46 1.41 (0.20, 9.91) 0.73 Hyperlipidaemia 5.47 (0.70, 42.90) 0.11 5.95 (0.70, 50.78) 0.10 Smoking 1.01 (0.32, 3.16) 0.99 0.61 (0.14, 2.73) 0.52 Stent diameter 1.04 (0.29, 3.68) 0.95 0.67 (0.12, 3.71) 0.65 Stent length 1.04 (0.96, 1.12) 0.36 1.04 (0.95, 1.13) 0.44 NCCT/5 mm group CAC score >209 9.89 (2.97, 32.92) <0.001 21.89 (4.19, 114.35) <0.001 Age >65 years 1.38 (0.46, 4.12) 0.56 0.63 (0.14, 2.74) 0.54 Male sex 1.23 (0.37, 4.11) 0.74 3.63 (0.52, 25.46) 0.20 Hyperlipidaemia 5.13 (0.65, 40.58) 0.12 9.74 (0.99, 95.99) 0.051 Smoking 0.78 (0.27, 2.30) 0.66 0.31 (0.05, 1.72) 0.18 Stent diameter 0.60 (0.14, 2.52) 0.49 0.32 (0.05, 2.01) 0.23 Stent length 1.08 (0.99, 1.18) 0.095 1.07 (0.97, 1.19) 0.19 CAC, coronary artery calcium; CCTA, coronary computed tomographic angiography; CI, confidence interval; NCCT, non-contrast chest computed tomography; OR, odds ratio. aggressive interventional approaches, such as cutting This work was supported by the National Natural Science Foundation of China (81830010, 81770428); ballooning [21], rotational atherectomy [21,22], orbital atherectomy [23], excimer laser coronary atherectomy Shanghai Science and Technology Committee [24] and coronary intravascular lithotripsy [25]. These (18411950400); Emerging and Advanced Technology approaches could be planned even before conducting Programs of Hospital Development Center of Shanghai (SHDC12018129); and Shanghai Sailing Program the invasive procedure. Our study provided a clinically useful tool of preprocedural assessment on CAC severity (20YF1444200, 19YF1444600). for tailoring interventional strategy. Conflicts of interest There are some limitations in this study. First, as a ret- There are no conflicts of interest. rospective study, there is selection bias. For example, there is a selected group of patients who underwent References coronary CT. Second, the sample size of this study is 1 Torrado J, Buckley L, Durán A, Trujillo P, Toldo S, Valle Raleigh J, et al. Restenosis, stent thrombosis, and bleeding complications: navigating limited. However, the findings were statistically sig- between scylla and charybdis. J Am Coll Cardiol 2018; 71:1676–1695. nificant and consistent among different subgroup anal- 2 Moussa ID, Mohananey D, Saucedo J, Stone GW, Yeh RW, Kennedy KF, yses. Larger-scale studies are warranted for further et al. Trends and outcomes of restenosis after coronary stent implantation in the United States. J Am Coll Cardiol 2020; 76:1521–1531. confirmation. 3 Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol 2010; In conclusion, our study found that either a CAC 56:1897–1907. score >245 in CCTA/2.5  mm or a CAC score >209 in 4 Henneke KH, Regar E, König A, Werner F, Klauss V, Metz J, et al. Impact NCCT/5  mm was independently associated with a of target lesion calcification on coronary stent expansion after rotational atherectomy. Am Heart J 1999; 137:93–99. higher risk in ISR. Further investigations are warranted 5 Fujino A, Mintz GS, Matsumura M, Lee T, Kim SY, Hoshino M, et al. A new to prospectively validate these findings and test the clin- optical coherence tomography-based calcium scoring system to predict ical usefulness of the CAC score assessed by CCTA or stent underexpansion. EuroIntervention 2018; 13:e2182–e2189. 6 Wang X, Matsumura M, Mintz GS, Lee T, Zhang W, Cao Y, et al. In vivo NCCT in optimizing interventional strategy for severely calcium detection by comparing optical coherence tomography, intra- calcified lesions. vascular ultrasound, and angiography. JACC Cardiovasc Imaging 2017; 10:869–879. 7 Maejima N, Hibi K, Saka K, Akiyama E, Konishi M, Endo M, et al. Acknowledgements Relationship between thickness of calcium on optical coherence tomogra- The authors thank Dr. Weituo Zhang from the School phy and crack formation after balloon dilatation in calcified plaque requiring of Medicine, Shanghai Jiao Tong University, Shanghai, rotational atherectomy. 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Anti-Cancer DrugsWolters Kluwer Health

Published: Jun 25, 2022

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