Prognostic implications of quantitative flow ratio and optical coherence tomography-guided neointimal characteristics in drug-coated balloon treatment for in-stent restenosis

doi:10.21203/rs.3.rs-4946365/v1

The aim of this study was to investigate the relationship between quantitative flow ratio (QFR) after drug-coated balloon (DCB) treatment for in-stent restenosis (ISR) and between neointimal characteristics assessed by optical coherence tomography (OCT) and clinical outcomes. This single-center, retrospective, observational cohort study included ISR patients who underwent DCB angioplasty under OCT guidance. The primary outcome of the study was a patient-oriented composite endpoint (POCE), defined as a composite endpoint of all-cause mortality, any stroke, any myocardial infarction, or any revascularization.During a median follow-up of 630 (IQR: 397–886) days, 147 ISR patients underwent OCT-guided DCB angioplasty, resulting in POCE development in 20 patients. At the post-procedural DCB angioplasty, the vessel-level QFR was significantly lower in the POCE group(0.88 [IQR:0.87, 0.90] vs 0.93 [IQR: 0.91, 0.95]; P < 0.001) than in the non-POCE group. Analysis of the qualitative characteristics of ISR lesions showed a significantly higher incidence of heterogeneous neointima in the POCE group compared with the non-POCE group (10 [50.00%] vs 12 [9.45%]; P < 0.001). In the multivariable Cox regression analysis, low vessel-level QFR (HR per 0.1 increase: 0.11; 95% CI: 0.03–0.39;P < 0.001) and heterogeneous neointima were independently associated with POCE. The POCE rate of vessels with the 2 features was 17.94 times higher than that of all other vessels (95%CI [2.91–110.6]; log-rank P < 0.001). Vessel-level QFR and heterogeneous neointima were independent factors associated with POCE in ISR patients after DCB angioplasty. Adding the QFR measure-ment to OCT findings may enable better discrimination of patients with subsequent POCE post-DCB angioplasty for ISR.

Health sciences/Cardiology

Health sciences/Diseases

in-stent restenosis(ISR)

drug-coated balloon (DCB)

quantitative flow ratio (QFR)

optical coherence tomography (OCT)

The incidence of in-stent restenosis (ISR) is currently rising by 1% to 2% per year¹^-². Extensive studies of ISR treatment strategies have recommended the drug-coated balloon (DCB) as a Class I A treatment option³. However, adverse events continue to affect prognosis after DCB angioplasty, and effective methods for predicting these events are lacking, highlighting a significant issue.

The quantitative flow ratio (QFR), an innovative computational physiology tool based on three-dimensional anatomical reconstruction and hemodynamic simulation, has demonstrated strong correlation with the invasive wire flow reserve fraction (FFR), improving the diagnostic accuracy of functional stenosis identification through coronary angiography⁴. In contrast, optical coherence tomography (OCT) offers micron-scale resolution and exceptional lumen imaging capabilities, delivering unique insights into quantitative measurements and qualitative assessments⁵^-⁶. However, the prognostic implications of the severity of physiological lesions assessed by QFR and neointimal characteristics evaluated by OCT remain unclear. This study aimed to explore the relationship between vessel-level QFR after DCB treatment for ISR and neointimal characteristics evaluated by OCT, along with their association with clinical outcomes.

Study design,population and study endpoints.

This study is a single-center, retrospective observational cohort analysis. Between January 2020 and September 2023, ISR is defined as a diameter narrowing of over 50% in the proximal or distal segments of the stent, as determined by angiography². The exclusion criteria for this study included: poor angiographic image quality preventing QFR measurements, poor OCT image quality, lost OCT images and loss to follow-up. Ultimately, 147 diseased vessels from 147 patients with in-stent restenosis were included in the analysis (Supplemental Figure 1). Baseline characteristics, QFR measurements before and after DCB angioplasty, OCT imaging prior to and following DCB angioplasty, and clinical follow-up data were analyzed. This study adhered to the ethical guidelines of the 1964 Declaration of Helsinki, received approval from the Ethics Committee of the Affiliated Hospital of Zunyi Medical University, and obtained written informed consent from all participants.

Clinical follow-up was conducted through outpatient visits, telephone contact, or structured follow-up. The primary outcome of the study was a patient-oriented composite endpoints (POCE), defined as the occurrence of all-cause mortality, any stroke, any myocardial infarction, or any revascularization according to the Academic Research Consortium-2 (ARC-2) consensus⁷. Further details regarding study endpoint definitions are provided in Supplemental Appendix 1.

Clinical baseline data, angiographic characteristics and percutaneous coronary nterventions(PCI) procedures

Clinical baseline data were collected from the hospital's electronic medical record system. This data consists of two main parts: 1. Demographic characteristics of the patients, including gender, age, blood pressure, body mass index, diabetes mellitus, smoking history, bleeding risk, hypertriglyceridemia, history of hypercholesterolemia, and peripheral artery disease. In addition, the patient's medication use after discharge was recorded. 2.Laboratory analysis included left ventricular ejection fraction and related hematological indicators, including white blood cell count, platelet count, triglycerides, total cholesterol, and markers of myocardial infarction. Details regarding angiographic and PCI procedures analysis are provided in Supplemental Appendix 1.

Off-line QFR computation

Calculating the QFR required uploading two angiographic images with angles of ≥25° to the AngioPlus software (Pulse Medical Imaging Technology, Shanghai, China) via a local network. Offline QFR calculations were performed using a previously described algorithm that included automatic depiction of the lumen contour by a thoroughly validated method. Manual corrections were allowed for cases where the angiographic image quality remained suboptimal after standard operating procedures (Figure 1). In this study, a frame counting method was used to derive contrast flow rates from coronary angiograms for QFR calculation. QFR analysis was performed by well-trained technicians⁸.

OCT image acquisition and analysis

All patients underwent OCT before and after DCB angioplasty. The procedure involved an intracoronary nitrate injection, followed by image acquisition using an OCT catheter (Dragonfly Duo, St. Jude Medical) and a frequency-domain OCT system (ILUMIEN OPTIS Intravessel-level Imaging System; St. Jude Medical, Inc., St. Paul, MN, USA). After delivering the OCT catheter along the guide wire to the distal part of the ISR lesion, it is advisable to advance beyond the stent segment and inject a contrast agent at a rate of 3-5 ml/sec to replace the blood in the target vessel, facilitating a clear, blood-free environment for optimal imaging. The retraction and rotation rates were set to 18 mm/s and 100 frames/s, respectively. The total length of the OCT pullback is approximately 75 mm. To ensure optimal quality of the collected OCT images, the procedure was performed by an experienced interventional cardiologist. To ensure the accuracy of the OCT image analysis, two experienced clinicians, blinded to the baseline clinical and angiographic lesion characteristics, were selected for independent analysis. In cases of disagreement, a third independent clinician was consulted to reach a consensus⁹. For a detailed analysis of the quantitative and qualitative features of OCT, please refer to Supplemental Appendix 1, and the neointimal chaaracteristics of OCT are shown in Figure 2.

Statistical analyses

To accurately assess the characteristics of the collected patient data, we classified the data into categorical and numerical variables. Categorical variables were presented as frequencies and percentages, and comparisons were made using the chi-square test or Fisher's exact test, when applicable. Continuous numerical variables were represented using different methods based on their distribution: normal distribution as mean ± standard deviation, and skewed distribution as median and interquartile range (IQR). Continuous numerical variables were compared between groups according to their distribution using the Student's t-test or Mann-Whitney U test. Additionally, receiver operating characteristic (ROC) curves were constructed to calculate the area under the curve and determine the optimal cut-off value for post-procedural QFR, assessing its predictive value for POCE after drug balloon angioplasty. The time to clinical outcome for each neointima and post-procedural QFR was assessed using Kaplan-Meier survival curves, and event-free survival curves were compared with a log-rank test. Independent factors associated with POCE were identified through Cox regression analysis. Logistic regression was conducted to identify independent factors associated with low vessel-level QFR (below the optimal cut-off) following post-DCB angioplasty. Finally, to evaluate the additive value of pre-DCB angioplasty OCT findings and post-DCB angioplasty vessel-level QFR in identifying patients with subsequent POCE, we compared the improvement in the discriminatory and reclassification ability of models that included these factors against a model using only baseline characteristics. Data analysis for this study was conducted using SPSS software (version 29.0; IBM Corp, Armonk, NY, USA) and R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria), employing a two-sided significance test with a threshold of P < 0.05.

During a median follow-up of 630 days (IQR: 397-886), a total of 147 patients with ISR underwent OCT-guided DCB angioplasty.A total of 20 patients experienced POCE during the follow-up period. The specific distribution of POCE included: all-cause death (3 patients), target vessel revascularization (13 patients), non-target vessel revascularization (1 patient), and acute stroke (3 patients). Patients were classified into the POCE group (n=20) and the non-POCE group (n=127).

Comparisons between the POCE and Non-POCE groups.

A comparison of baseline data between the groups revealed that the POCE group had significantly lower diastolic blood pressure (68.00 [IQR: 62.00, 76.50] vs. 76.00 [IQR: 68.00, 84.50]; P = 0.017) and lower body mass index (23.37 [IQR: 22.24, 25.12] vs. 23.02 [IQR: 23.02, 26.90]; P = 0.024) compared to the non-POCE group (Table 1).

In the comparison of angiographic characteristics, the POCE group had a lower reference lumen diameter (2.24 [IQR: 1.97, 2.46] vs. 2.51 [IQR: 2.26, 2.90]; P = 0.008) compared to the non-POCE group. The vessel-level QFR pre- and post-DCB angioplasty was compared between the two groups. After the DCB angioplasty, the vessel-level QFR was significantly lower in the POCE group (0.88 [IQR: 0.87, 0.90] vs. 0.93 [IQR: 0.91, 0.95]; P < 0.001) than in the non-POCE group. After the DCB angioplasty, the vessel-level QFR was significantly lower in the POCE group (0.88 [IQR: 0.87, 0.90] vs. 0.93 [IQR: 0.91, 0.95]; P < 0.001) than in the non-POCE group. The improvement in vessel-level QFR was significantly lower in the POCE group (0.10 [IQR: 0.07, 0.15] vs. 0.14 [IQR: 0.09, 0.29]; P = 0.011) compared to the non-POCE group (Table 2).

Table 3 summarizes the quantitative and qualitative results of pre- and post-procedural DCB angioplasty in patients with ISR. Regarding quantitative characteristics, the proximal reference lumen diameter before DCB angioplasty was lower in the POCE group than in the non-POCE group (2.86 [IQR: 2.76-3.18] vs. 3.19 [IQR: 2.96-3.15]; P = 0.027). The maximum neointimal thickness in the POCE group was lower than that in the non-POCE group (0.83 ± 0.21 vs. 0.99 ± 0.25; P = 0.011). Post-procedural quantitative analysis showed that the maximum neointimal thickness improvement in the POCE group was significantly lower than in the non-POCE group (0.38 ± 0.16 vs. 0.48 ± 0.20; P = 0.038). Furthermore, the analysis of qualitative characteristics of ISR lesions revealed a significantly higher incidence of heterogeneous neointima in the POCE group than in the non-POCE group (10 [50.00%] vs. 12 [9.45%]; P < 0.001;Supplemental Figure 2 ).

Factors associated with POCE.

The results of the univariable and multivariable Cox regression analyses for TVF are presented in Table 4. Variables with P < 0.1 in the univariable analysis were included in the multivariable Cox regression analysis. The multivariable model indicated that diastolic blood pressure, monocyte count, post-procedural vessel-level QFR, maximal neointimal thickness improvement, and heterogeneous neointima were independently associated with POCE.

Among the factors independently associated with POCE, post-procedural vessel-level QFR and heterogeneous neointima are the most critical. Receiver operating characteristic curve analysis revealed that the cutoff value of vessel-level QFR for identifying patients with subsequent POCE was 0.895 (sensitivity: 86.6%; specificity: 70%; area under the curve: 0.875; 95% confidence interval: 0.804-0.945; p < 0.001; Supplemental Figure 3). The incidence of POCE was 11.07 times higher in vessels with low vessel-level QFR (< 0.895) compared to those with high vessel-level QFR (≥ 0.895) (95% CI [3.49-35.18]; log-rank P < 0.001; Supplemental Figure 4). The cumulative POCE rate analysis showed that the incidence of POCE in heterogeneous neointima was significantly higher than in the other three types of neointima (log-rank P < 0.001; Supplemental Figure 5A). These three types were classified as non-heterogeneous neointima. The incidence of POCE in heterogeneous neointima was 7.85 times higher than in non-heterogeneous neointima (95% CI [1.97-31.33]; log-rank P < 0.001;Supplemental Figure 5B). The POCE rate was highest in vessels with both features, followed by those with one feature and those without either feature (Figure 3A). The POCE rate in vessels with both features was 17.94 times higher than in all other vessels (95% CI [2.91-110.6]; log-rank P < 0.001) (Figure 3B).

Factors associated with low vessel-level QFR (<0.895).

Multivariable logistic regression analysis revealed that post-procedural maximum neointimal thickness (OR: 0.016, 95% CI [0.00-0.53]; P = 0.021) and heterogeneous neointima (OR: 13.19, 95% CI [3.52-49.36]; P < 0.001) were independently associated with low vessel-level QFR (< 0.895) (Supplemental Table 1).

Incremental value of vessel-level QFR in identifying patients with subsequent POCE.

Figure 4 presents the C-index, net reclassification index, and relative integrated discrimination improvement values for the three models. In comparison to model 1 (diastolic blood pressure and monocyte count), model 2 (model 1 plus pre-procedural OCT findings) demonstrated significantly greater discriminatory ability (C-index: 0.856 vs 0.670; P < 0.001) and reclassification ability (net reclassification index: 0.559; P = 0.018; relative integrated discrimination improvement: 0.193; P = 0.003) for identifying patients with subsequent POCE. Compared to model 2, model 3 (model 2 plus vessel-level QFR) exhibited an even greater discriminatory ability (C-index: 0.918 vs 0.856; P < 0.001) and incremental reclassification ability (net reclassification index: 1.027; P < 0.001; relative integrated discrimination improvement: 0.175; P = 0.003).

The main findings of this study are as follows: (1) Post-procedural vessel-level QFR and heterogeneous neointima observed via OCT were independent predictors of POCE after DCB angioplasty in patients with ISR. (2) Vessel-level QFR was significantly lower in the POCE group compared to the non-POCE group following DCB angioplasty in patients with ISR. (3) The optimal cut-off value for predicting QFR in POCE is 0.895; additionally, post-procedural maximum neointimal thickness and heterogeneous neointima are independently associated with low vessel-level QFR (<0.895). (4) The incidence of POCE in ISR patients with low vessel-level QFR and heterogeneous neointima after DCB angioplasty is 17.94 times higher than that in all other vessels. (5) Vessel-level QFR post-DCB angioplasty in patients with ISR provides additional predictive value beyond morphological OCT outcomes for identifying patients at risk for subsequent POCE.

DCB angioplasty is one of the most effective therapeutic strategies for ISR and exemplifies the concept of intervention without stent placement. The mechanism involves using a balloon coated with an antiproliferative drug, which is inflated at the lesion site under specific pressure. This process allows for rapid and uniform transfer of the drug through the lipophilic matrix into the vessel wall, eliminating the need for a permanent implant¹⁰. Consequently, the duration of dual antiplatelet therapy is shortened, and the risk of chronic inflammation in the vessel wall is reduced, thereby minimizing the risks of bleeding and revascularization. However, adverse clinical events following DCB angioplasty cannot be overlooked, highlighting the need for appropriate predictive indicators to optimize DCB strategies.

Currently, FFR is the gold standard for determining the need for PCI in patients with coronary artery disease. Previous studies have demonstrated an inverse relationship between post-PCI FFR and future adverse cardiac events. The accepted FFR cut-off for identifying a hemodynamic-related lesion is 0.8³.However, the disadvantages of FFR, including its invasive nature and the requirement for pharmacologically induced congestion, contribute to higher costs and result in its underutilization in clinical practice. To address these limitations, QFR was developed to facilitate the calculation of functional parameters more simply and rapidly¹¹. Studies have shown a strong correlation and consistency between QFR and FFR, using FFR as the reference standard¹²^-¹³. This indicates that QFR has significant potential for prognostic assessment, making it crucial to measure QFR values after PCI. A study by Biscaglia et al¹⁴^. showed that low QFR values after PCI are independent predictors of adverse events, establishing an optimal cut-off of 0.89 for QFR after PCI. Similarly, research by Ki et al¹⁵. and others demonstrated that lesions with low QFR (< 0.90) are associated with a significantly higher risk of adverse events. Since none of these studies focused on ISR lesions, Liontou et al¹⁶.examined the diagnostic performance of QFR in ISR lesions, using FFR as a reference standard, and found that QFR exhibited high diagnostic performance similar to that of primary lesions. The application of post-procedural physiological assessment was subsequently extended to DCB angioplasty in ISR lesions, with clinical outcomes analyzed yielding consistent results¹⁷^-¹⁸. Our study also reconfirmed these findings, with optimal cut-off values aligning with previous research. Unlike FFR, QFR can be computed using only quantitative lumen information from angiographic images to derive virtual FFR. Therefore, QFR values for ISR lesions after DCB angioplasty are straightforward, efficient, and feasible for predicting clinical adverse events.

OCT is a well-established method for imaging intracoronary structures. Unlike conventional angiography, which provides only basic information about the shape of the vessel lumen without insight into the inner wall, OCT addresses this limitation by offering a comprehensive view of the diseased vessel's inner wall. It provides detailed tomographic or cross-sectional images of the coronary arteries, including data on the lumen, vessel wall, plaque burden, and the composition and distribution of plaque. This advancement has significantly improved the prognosis for patients undergoing PCI¹⁹^-²⁰. This method has been utilized to characterize the vessel-level responses following PCI, thereby enhancing our understanding of the development of ISR. Recently, the neointima in ISR lesions identified via OCT has been primarily categorized into homogeneous, heterogeneous, layered neointima, and neoatherosclerosis²¹^-²². Previous research has demonstrated a significant correlation between the chosen treatment approach and neointima patterns, highlighting the superiority of drug-eluting stents (DES) over DCB in cases of heterogeneous neointima²³^-²⁴. This study further confirmed the poorer prognosis associated with DCB for treating heterogeneous neointima. Therefore, it is expected that a detailed examination of ISR lesion characteristics and the development of a scientific treatment strategy will positively impact treatment outcomes.

Recently, incorporating physiological indicators derived from hemodynamics alongside the morphological characteristics observed by OCT for combined prediction has shown to significantly enhance the predictive ability for clinical outcomes¹⁵^,²⁵. Furthermore, our research strongly supports the applicability of this combined predictor in cases of ISR lesions treated with DCB. To validate the practicality of this finding, further prospective studies with larger sample sizes are recommended.

Study limitations

This study is a retrospective analysis conducted at a single center, which inherently includes limitations associated with its design. First, we excluded patients with poor-quality angiography and OCT images, leading to unavoidable selection bias. Second, the primary outcome of interest, POCE is a composite outcome, and the factors associated with it may differ across various clinical outcomes. Due to the relatively small sample size, we are unable to evaluate each clinical outcome separately and cannot ascertain any differences between them. Third, the study is a post-hoc analysis, and the QFR computation was performed offline, which may affect the accuracy of the QFR values. However, previous studies have demonstrated good consistency between offline and online measurements. Finally, the results of this study should be regarded as exploratory; further prospective studies are needed to determine whether physiological methods based on QFR and morphological methods based on OCT can improve clinical outcomes for patients receiving DCB treatment for ISR.

This study demonstrated that vessel-level QFR and heterogeneous neointima were independent factors associated with POCE in ISR patients after DCB angioplasty. Incorporating QFR measurements alongside OCT findings enhances the ability to discriminate patients at risk for subsequent POCE after DCB angioplasty for ISR. A comprehensive assessment of vessel-level QFR and neointimal characteristics may lead to improved clinical outcomes for DCB treatment in ISR patients.

ARC	Academic Research Consortium
AUC	area under the curve
CAG	coronary angiography
CI	confidence interval
DCB	drug-coated balloon
DES	drug-eluting stents
FFR	fractional flow reserve
HR	hazard ratio
IQR	interquartile range
ISNA	in-stent neoatherosclerosis
ISR	in-stent restenosis
OCT	Optical coherence tomography
OR	oddis ratio
PCI	percutaneous coronary interventions
POCE	patient-oriented composite endpoints
QCA	quantitative coronary angiography
QFR	quantitative flow ratio
ROC	receiver operating characteristic curves
TCFA	thin-cap fibroatheroma

Data availability

Due to privacy and ethical constraints, the datasets generated and analysed in this study are not publicly available but can be obtained from the corresponding author.

Supplemental Information

Please see the instructions for preparation and submisison of Supplemental information.

Acknowledgments

We thank all the members who contributed to this study.

Authors’ contributions

Zhenglong Wang and Bei Shi conceived the study. Shiwan Lu, Li Pan and Ning Gu did the

OCT analysis.Yi Deng, Chancui Deng, Xiushi Li and Feng Wang performed the statistical analysis and interpreted the study results. Shiwan Lu wrote the first draft of the manuscript, which was critically revised for important intellectual content by Yongchao Zhao. All authors read and approved the final manuscript.

Funding

This work was funded by the Regional Fund Project of the National Natural Science Foundation of China (project name: Differential expression of DC-derived lncRNAs in acute coronary syndrome and their regulatory mechanism; project number: 81760072), the Guizhou Provincial Basic Research Program (Natural Science) (Qiankehe Foundation-ZK [2024] Key 085).

Competing interestsThe authors declare no competing interests.

Ethical approval

The protocol was approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Supplemental & Information.
Please see the. instructions for preparation and submisison of Supplemental information.

Table1 Baseline Clinical and Laboratory Characteristics

	POCE (n=20)	Non-POCE (n=127)	P Value
Age,M ± SD,years	64.65 ± 10.97	61.97 ± 10.38	0.288
Male,n(%)	14 (70.00)	98 (77.17)	0.677
Heart rate,M ± SD,beats/min	75.65 ± 9.83	75.76 ± 12.39	0.971
Systolic blood pressure,,M ± SD,mmHg	123.35 ± 18.04	127.72 ± 21.46	0.389
Diastolic blood pressure,M(IQR), mmHg	68.00 (62.00, 76.50)	76.00 (68.00, 84.50)	0.017
BMI, M(IQR), kg/m²	23.37 (22.24, 25.12)	24.84 (23.02, 26.90)	0.024
Comorbidity,n(%)
Hypertension,n(%)	11 (55.00)	76 (59.84)	0.682
Diabetes mellitus,n(%)	6 (30.00)	48 (37.80)	0.501
Hypertriglyceridemia,n(%)	8 (40.00)	63 (49.61)	0.424
Hypercholesterolemia,n(%)	5 (25.00)	31 (24.41)	1.000
Smoking history,n(%)	7 (35.00)	58 (45.67)	0.372
Chronic kidney disease,n(%)	4 (20.00)	18 (14.17)	0.733
Peripheralartery disease,n(%)	3 (15.00)	6 (4.72)	0.201
Previous stroke history,n(%)	2 (10.00)	3 (2.36)	0.137
Clinical presentation
Stable ischemic heart disease,n(%)	0 (0.00)	2 (1.57)	1.000
Acute coronary syndrome,n(%)	9 (45.00)	73 (57.48)	0.296
Discharge therapy
Aspirin,n(%)	18 (90.00)	97 (76.38)	0.280
Indobufen,n(%)	2 (10.00)	28 (22.05)	0.345
P2Y12 inhibitors
Clopidogrel,n(%)	15 (75.00)	86 (67.72)	0.514
Ticagrelor,n(%)	5 (25.00)	39 (30.71)	0.604
Atorvastatin,n(%)	20 (100.00)	109 (85.83)	0.153
Rosuvastatin,n(%)	0 (0.00)	17 (13.39)	0.173
Ezetimibe Tablets,n(%)	1 (5.00)	17 (13.39)	0.486
PCSK9-inibitor,n(%)	2 (10.00)	21 (16.54)	0.677
Beta-blockers,n(%)	19 (95.00)	103 (81.10)	0.223
ACEI/ARB,n(%)	17 (85.00)	103 (81.10)	0.914
Calcium-channel blockers,n(%)	1 (5.00)	10 (7.87)	1.000
Laboratory results
LVEF,M(IQR),	60.00 (43.25, 61.00)	59.00 (51.50, 61.00)	0.980
WBC count,M(IQR), ×10⁹/L	7.37 (6.01, 9.35)	6.79 (5.45, 7.76)	0.172
Neutrophil count,M(IQR), ×10⁹/L	4.96 (3.93, 5.93)	4.42 (3.43, 5.21)	0.147
Monocyte count,M(IQR),×10⁹/L	0.51 (0.43, 0.80)	0.50 (0.37, 0.63)	0.297
Lymphocyte count,M(IQR),×10⁹/L	1.52 (1.23, 1.98)	1.58 (1.16, 1.88)	0.834
Hb,M ± SD,g/L	138.75 ± 18.40	140.09 ± 16.81	0.743
Platelet count,×10⁹/L	185.50 (142.50, 217.25)	185.00 (151.00, 235.00)	0.441
RBC count, M(IQR),×10¹²/L	4.53 ± 0.74	4.62 ± 0.62	0.561
RBC distribution,M(IQR)	13.40 (12.90, 14.33)	13.20 (12.80, 13.90)	0.378
ApolipoproteinA1, M(IQR),g/L	1.15 (1.10, 1.29)	1.20 (1.10, 1.35)	0.530
ApolipoproteinB,M(IQR), g/L	0.73 (0.63, 0.85)	0.69 (0.57, 0.90)	0.623
Triglycerides, M(IQR),mmol/L	1.59 (1.20, 2.26)	1.62 (1.17, 2.75)	0.403
Total cholesterol,M(IQR),mmol/L	4.05 (3.50, 4.87)	3.84 (3.26, 4.83)	0.674
HDL-C,M(IQR),mmol/L	1.14 (0.99, 1.23)	1.05 (0.91, 1.20)	0.135
LDL-C,M(IQR),mmol/L	2.34 (1.90, 2.90)	2.18 (1.83, 2.83)	0.532
Myoglobin,M(IQR),ng/ml	33.00 (22.00, 45.75)	31.00 (20.50, 42.52)	0.645
Hs-cTn,M(IQR),ng/ml	15.45 (8.53, 42.89)	14.06 (8.09, 23.54)	0.549
Uric acid,M(IQR),mmol/L	343.50 (308.75, 364.50)	355.00 (319.00, 412.00)	0.181
Urea,M(IQR),mmol/L	5.58 (4.53, 7.05)	5.90 (4.75, 7.20)	0.599
Creatinine,M(IQR),μmmol/L	76.00 (69.50, 100.00)	85.00 (70.00, 100.00)	0.692
BNP, M(IQR),ng/L	294.40 (91.25, 1188.75)	157.50 (68.62, 625.00)	0.273

POCE=patient-oriented composite endpoints; M ± SD = mean ± stand deviation; M(IQR) = median(interquartile range); BMI = body mass index; PCSK9-inibitor = proprotein convertase subtilisin/kexin type 9 inibitor; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVEF = left ventricular ejection fraction; WBC = white blood cell；Hb =haemoglobin; RBC = red blood cell; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Hs-cTn = high-sensitivity cardiac troponin; BNP = brain natriuretic peptide.

Table 2 Baseline Angiographic, and Procedural Characteristics

	POCE （n=20）	Non-POCE （n=127）	P Value
angiographic features
Multivessel disease,n(%)	17 (85.00)	92 (72.44)	0.233
ISR location
LAD,n(%)	10 (50.00)	78 (61.42)	0.333
LCX,n(%)	2 (10.00)	12 (9.45)	1.000
RCA,n(%)	8 (40.00)	37 (29.13)	0.327
Lesional segment
Proximal,n(%)	6 (30.00)	46 (36.22)	0.589
Middle,n(%)	10 (50.00)	64 (50.39)	0.974
Distal,n(%)	4 (20.00)	17 (13.39)	0.659
Restenosis pattern
Mehran I,n(%)	0 (0.00)	13 (10.24)	0.282
Mehran II,n(%)	10 (50.00)	59 (46.46)	0.768
Mehran III,n(%)	7 (35.00)	41 (32.28)	0.810
Mehran IV,n(%)	3 (15.00)	14 (11.02)	0.888
Pre-DCB angioplasty QCA
Reference vessel diameter,M(IQR), mm	2.24 (1.97, 2.46)	2.51 (2.26, 2.90)	0.008
Minimal lumen diameter,M ± SD, mm	1.17 ± 0.32	1.29 ± 0.39	0.199
Diameter stenosis,M ± SD, %	48.62 ± 8.52	50.16 ± 12.34	0.488
Area stenosis, M(IQR), %	72.05 (67.07, 80.58)	75.80 (64.45, 83.25)	0.437
Lesion length, M(IQR), mm	21.25 (14.76, 34.55)	18.91 (12.78, 26.55)	0.133
Post-DCB angioplasty QCA
Minimal lumen diameter,M(IQR), mm	1.94 (1.82, 2.05)	1.87 (1.65, 2.11)	0.645
Diameter stenosis,M± SD,%	24.52 ± 6.28	24.79 ± 6.91	0.872
Area stenosis,M ± SD, %	42.19 ± 9.31	42.94 ± 10.18	0.756
Acute lumen gain,M(IQR), mm	0.77 (0.61, 0.98)	0.65 (0.26, 1.04)	0.238
Pre-DCB angioplasty data:
Predilation,M(IQR),atm	13.00 (11.00, 15.00)	13.00 (12.00, 15.00)	0.758
DCB length,M(IQR), mm	25.00 (20.00, 30.00)	25.00 (20.00, 30.00)	0.505
DCB diameter,M(IQR), mm	3.00 (2.75, 3.50)	3.00 (3.00, 3.50)	0.210
DCB pressure,M(IQR), atm	10.00 (8.75, 12.00)	10.00 (8.00, 12.00)	0.423
DCB Inflation time ,M(IQR), s	60.00 (60.00, 60.00)	60.00 (60.00, 70.00)	0.513
Procedural time,M(IQR), min	93.00 (66.75, 117.25)	90.00 (70.50, 112.00)	0.946
Contrast agent,M(IQR), ml	250.00 (200.00, 285.00)	250.00 (200.00, 300.00)	0.408
Pre-DCB angioplasty TIMI flow grade,M(IQR)	3.00 (3.00, 3.00)	3.00 (3.00, 3.00)	0.741
Vessel-level QFR
Pre-DCB angioplasty QFR,M(IQR)	0.80 (0.74, 0.81)	0.79 (0.63, 0.84)	0.836
Post-DCB angioplasty QFR,M(IQR)	0.88 (0.87, 0.90)	0.93 (0.91, 0.95)	<0.001
QFR improvement,M(IQR)	0.10 (0.07, 0.15)	0.14 (0.09, 0.29)	0.011

POCE = patient-oriented composite endpoints; ISR = in-stent restenosis; LAD = left anterior descending artery; LCX = left circumflex artery; RCA = right coronary artery; DCB = drug-coated balloon; QCA = quantitative coronary angiography; M(IQR) = median(interquartile range); M ± SD = mean ± stand deviation;TIMI = thrombolysis in myocardial infarction;QFR = quantitative flow ratio.

Table 3 Optical Coherence Tomography Characteristics

	POCE （n=20）	Non-POCE （n=127）	P Value
Quantitative variables
Pre-DCB angioplasty
Distal reference vessel diameter,M ± SD, mm	2.50 ± 0.53	2.57 ± 0.45	0.493
Proximal reference vessel diameter,M(IQR), mm	2.86 (2.76, 3.18)	3.19 (2.96, 3.35)	0.027
Minimal luminal diameter,M ± SD, mm	1.44 ± 0.32	1.56 ± 0.33	0.122
Minimal luminal area,M± SD,mm²	1.73 ± 0.76	2.01 ± 0.83	0.150
Area stenosis,M(IQR), %	63.05 (59.80, 71.83)	66.40 (58.05, 71.25)	0.788
Lesion length,M ± SD, mm	19.48 ± 7.72	17.88 ± 8.43	0.428
Maximal neointimal thickness,M ± SD, mm	0.83 ± 0.21	0.99 ± 0.25	0.011
Post-DCB angioplasty
Minimal luminal diameter ,M ± SD, mm	2.34 ± 0.39	2.41 ± 0.40	0.459
Acute lumen gain,M ± SD, mm	0.90 ± 0.48	0.85 ± 0.38	0.595
Minimal luminal area,M± SD,mm²	4.44 ± 1.47	4.79 ± 1.46	0.323
Maximal neointimal thickness ,M ± SD, mm	0.45 (0.38, 0.50)	0.48 (0.35, 0.67)	0.439
Maximal neointimal thickness improvement, M ± SD, mm	0.38 ± 0.16	0.48 ± 0.20	0.038
Qualitative variables
Neointimal characteristics			＜0.001
Homogeneous,n(%)	5 (25.00)	47 (37.01)	0.297
Heterogeneous,n(%)	10 (50.00)	12 (9.45)	＜0.001
Layered,n(%)	3 (15.00)	31 (24.41)	0.521
Neoatherosclerosis,n(%)	2 (10.00)	37 (29.13)	0.072
Thin-cap fibroatheroma,n(%)	4 (20.00)	11 (8.66)	0.246
Calcified plaque,n(%)	2 (10.00)	5 (3.94)	0.243
Neointimal rupture,n(%)	5 (25.00)	12 (9.45)	0.100
Macrophage infiltration,n(%)	6 (30.00)	17 (13.39)	0.116

POCE = patient-oriented composite endpoints; DCB = drug-coated balloon;M±SD = mean±stand deviation;M(IQR) = median(interquartile range).

Table 4. Cox Regression Analyses for Factors Associated With POCE After DCB in Patients With ISR

	Univariable Regression			Multivariable Regression
	HR	95% CI	P Value	HR	95% CI	P Value
Diastolic blood pressure,mmHg	0.95	0.91-0.99	0.010	0.95	0.91-1.00	0.043
Peripheralartery disease	0.39	0.12-1.34	0.140
Previous stroke history	0.30	0.07-1.31	0.110
WBC count, ×10⁹/L	1.14	0.96-1.35	0.150
Neutrophil count, ×10⁹/L	1.17	0.94-1.46	0.160
Monocyte count,×10⁹/L	6.91	1.16-41.30	0.034	13.45	1.58-114.56	0.017
Triglycerides, mmol/L	0.72	0.46-1.14	0.160
HDL-C,mmol/L	3.13	0.70-14.09	0.140
Myoglobin,ng/ml	1.00	1.00-1.03	＜0.001
Hs-cTn,ng/ml	1.00	1-1.01	＜0.001
Pre-procedural QCA
Reference vessel diameter, mm	0.34	0.14-0.83	0.018
Physiological results
Post-DCB angioplasty QFR (per 0.1 increase)	0.09	0.03-0.23	＜0.001	0.11	0.03-0.39	＜0.001
OCT Quantitative variables
Pre-DCB angioplasty
Proximal reference vessel diameter (mm)	0.25	0.09-0.72	0.010
Minimal luminal diameter (mm)	0.31	0.08-1.30	0.110
Minimal luminal area(mm²)	0.63	0.34-1.16	0.140
Maximal neointimal thickness (mm)	0.06	0.01-0.41	0.004
Post-DCB angioplasty
Maximal neointimal thickness (mm)	0.18	0.01-2.37	0.190
Maximal neointimal thickness improvement	0.05	0.004-0.72	0.028	0.01	0.00-0.80	0.039
Qualitative variables
Neointimal characteristics
Homogeneous	1.53	0.55-4.21	0.410
Heterogeneous	0.11	0.45-0.27	＜0.001	0.26	0.09-0.75	0.013
Layered	1.99	0.58-6.79	0.270
Neoatherosclerosis	3.88	0.90-16.79	0.070
Thin-cap fibroatheroma	0.47	0.16-1.40	0.180
Calcified plaque	0.36	0.09-1.57	0.180
Neointimal rupture	0.36	0.13-1.01	0.051
Macrophage infiltration	0.47	0.18-1.23	0.130

POCE = patient-oriented composite endpoints; DCB = drug-coated balloon; ISR = in-stent restenosis; HR = hazard ratio; CI = confidence interval; WBC= white blood cell；HDL-C = high-density lipoprotein cholesterol; Hs-cTn = high-sensitivity cardiac troponin; QCA = quantitative coronary angiography; QFR = quantitative flow ratio; OCT = optical coherence tomography.

No competing interests reported.

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Prognostic implications of quantitative flow ratio and optical coherence tomography-guided neointimal characteristics in drug-coated balloon treatment for in-stent restenosis

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