pISSN 0513-5796   eISSN 1976-2437
Open Access, Peer-reviewed, Monthly
    Yonsei Med J. 2023 Oct;64(10):593-603. English.
    Published online Sep 13, 2023.
    https://doi.org/10.3349/ymj.2022.0606
    © Copyright: Yonsei University College of Medicine 2023
    Original Article

    Drug-Coated Balloons for De Novo Coronary Artery Lesions: A Meta-Analysis of Randomized Clinical Trials

    Dejin Wang, Xiqian Wang, Tianxiao Yang, Hongliang Tian, Yuanzhen Su and Qilei Wang
      • Department of Cardiology, Zibo Central Hospital, Zibo, Shandong, China.
    • Corresponding author: Qilei Wang, MM, Department of Cardiology, Zibo Central Hospital, No.54 Gongqingtuan West Road, Zhangdian District, Zibo City, Shandong Province 255036, China. Email: qileiwang2212@163.com
    Received January 30, 2023; Revised June 26, 2023; Accepted June 29, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Purpose

    Through meta-analysis, we aimed to assess the efficacy and safety of drug-coated balloons (DCB), compared with drug-eluting stents (DES) or uncoated devices, in the treatment of de novo coronary lesions.

    Materials and Methods

    Only randomized controlled trials were included. The primary outcomes were late lumen loss (LLL), target lesion revascularization (TLR), and major adverse cardiac events (MACEs). Subgroup analyses were conducted based on clinical indications, whether DCBs were used with a systematic or bailout stent, and types of DESs.

    Results

    The present meta-analysis demonstrated that DCBs elicit significantly lower incidences of TLR, MACE, and LLL, compared with uncoated devices, and similar incidences, compared with DESs, in the treatment of de novo coronary lesions. Subgroup analysis indicated that DCBs used with a bailout stent achieved lower incidences of binary restenosis and myocardial infarction, compared with uncoated devices, and provided less LLL than DESs. DCBs showed similar rates of TLR and MACE, with significantly less LLL, than DESs in treating de novo small-vessel diseases. The clinical efficacy of DCBs was similar to that of second-generation DES.

    Conclusion

    Overall, DCB is favored over bare metal stent alone in treating de novo coronary lesions. DCBs appear to be a promising alternative to DESs in the treatment of de novo coronary lesions.

    Graphical Abstract

    Keywords
    Coronary artery disease; drug-coated balloon; drug-eluting stents; bare metal stent; de novo lesions; small-vessel disease

    INTRODUCTION

    Coronary artery disease (CAD) is a major cause of mortality and morbidity worldwide, with percutaneous coronary intervention (PCI) being a commonly used treatment.1 Currently, drug-eluting stents (DESs) are the primary treatment option during PCI for CAD. However, their use is limited in certain CAD cases due to the risk of late stent thrombosis, restenosis, and impaired vasomotor function resulting from the presence of permanent metallic struts within the vessel and the need for prolonged dual antiplatelet therapy.2, 3, 4, 5, 6

    In this context, drug-coated balloon (DCB) technology is an appealing alternative. DCBs allow for rapid and homogenous delivery of anti-proliferative drugs into the vessel wall with single balloon inflation, without leaving a foreign body.7, 8 DCBs have been an established therapeutic option for in-stent restenosis (ISR) of bare metal stents (BMS) and DESs,9, 10, 11 and are endorsed as a class I recommendation by European Society of Cardiology guidelines.12 However, the safety and efficacy of DCB in de novo coronary lesions are still subjects of controversy. Previous randomized controlled trials (RCTs) have reported inconsistent results on the efficacy of DCB in comparison with other devices [e.g., plain old balloon angioplasty (POBA), BMS, and DES], with some trials demonstrating benefits,13, 14, 15, 16 but others show equivalence17, 18, 19 or even potential harm.20, 21, 22

    Against this background, the present meta-analysis aims to provide a comprehensive and quantitative assessment of the safety and efficacy of DCB in de novo coronary lesions.

    MATERIALS AND METHODS

    Search strategy

    Systematic databases, including PubMed, Web of Science, Scopus, Cochrane Library, and China National Knowledge Infrastructure (CNKI), were searched without any restriction on publication status or language for RCTs that investigated the roles of DCB for the treatment of de novo coronary lesions. The final search was performed in May 2022. Search terms, such as “drug eluting balloon,” “drug coated balloon,” “paclitaxel eluting balloon,” “randomized,” “trial,” “coronary artery disease,” and “small-vessel disease” were used separately and in combination. The bibliographies of the retrieved articles and relevant reviews were manually searched to identify additional trials that may have been missed in the initial search. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA).

    Inclusion criteria

    RCTs that enrolled patients with de novo coronary lesions and assessed the safety and efficacy of DCB in comparison with other interventions, including POBA, BMS, DES, on angiographic and clinical outcomes, were included. The minimum follow-up duration for assessing clinical and angiographic outcomes was 6 months. Non-randomized study designs, observational studies, trials that analyzed patients with indications other than de novo coronary lesions, and studies with irretrievable outcome data were excluded. Two authors independently assessed all potentially relevant studies. Any discrepancies were resolved by discussion.

    Data collection

    Two reviewers independently extracted data using a standardized data extraction form. Discrepancies among reviewers were resolved by consensus. The collected data included general study information (first author, study region, publication year, study design, sample size), baseline patients characteristics [mean age, sex distribution, risk factor including diabetes, hypertension, dyslipidemia, smoking, myocardial infarction (MI), previous PCI, clinical presentation], baseline lesion and angiographic characteristics [indication, lesion length, reference vessel diameter (RVD), minimal luminal diameter (MLD), diameter stenosis (DS)], treatment information (type of comparator, type of DCB or DES), and outcomes of interest.

    The outcomes were reported based on the intention-to-treat approach and at the time of the longest available follow-up. The primary outcomes were target lesion revascularization (TLR), major adverse cardiac events (MACE), and late lumen loss (LLL). Secondary clinical outcomes were target vessel revascularization (TVR), stent thrombosis, MI, cardiac mortality, and all-cause mortality. Secondary angiographic outcomes included MLD, DS, and binary restenosis.

    Quality assessment

    The modified Jadad scale for reporting RCTs was used to assess the quality of the included studies.23 The scale covers four domains: randomization, allocation concealment, double blinding, and withdrawals and dropouts. Studies with scores >3 were considered high-quality studies, while those with scores of 3 or less were considered low-quality studies.

    Statistics analysis

    Statistical analyses were preformed using Stata software version 15.0 (Stata Corporation, College Station, TX, USA). Baseline characteristics were computed as weighted means with standard deviations (SD) for continuous variables and weighted averages for categorical variables, using the sample size as the weight. Categorical variables were compared using Fisher’s exact or the chi-square test, while continuous variables were analyzed using the two-sample t-test. Binary data are summarized using odds ratio (OR) and 95% confidence interval (CI), whereas continuous data are summarized using weighted mean differences (WMD) with 95% CI. A two-tailed p-value <0.05 was considered as statistically significant. Between-study heterogeneity was assessed using I2 statistics, where values <25%, 25% to 50%, and >50% were considered to indicate low, moderate, and high heterogeneity, respectively.24 When high heterogeneity (I2 >50%) was detected, a random-effect Mantel-Haenszel model was used; otherwise, a fixed effect model was applied.

    Whenever possible, pooled analyses were conducted separately for all outcomes comparing DCB versus DES or DCB versus uncoated devices. The following prespecified subgroup and meta-regression analyses were conducted when data were sufficient: 1) based on clinical indications [small-vessel disease (SVD), MI, bifurcation lesions, high bleeding risk, and unspecific de novo lesions]; 2) based on whether DCB was used with a systematic stent or a bailout stent in case of flow-limiting dissection after DCB; and 3) based on types of DES (first and seconder generation). Between-subgroup interactions were also tested using meta-regression models, and a p-value <0.05 indicated a significant difference. Sensitivity analysis was conducted by removing one study outcome at a time to test the impact of each study on the heterogeneity and overall results. Potential publication bias was examined using Begg’s and Egger’s test and deemed significant when p<0.05. For outcomes that presented significant publication bias, the robustness of the pooled results was further assessed by trim-and-fill analysis.

    RESULTS

    Search results

    A total of 1483 papers were identified in the initial search, of which 78 were assessed for eligibility based on inclusion criteria. Ultimately, 33 independent RCTs were included in this meta-analysis. The complete list of references for the included studies is provided in Supplementary Material (only online). The PRISMA flow diagram depicting the process of study selection is presented in Fig. 1.

    Fig. 1
    PRISMA flow diagram depicting the process of study selection. RCTs, randomized controlled trials.

    Study characteristics

    Among the 33 RCTs, 24 provided available data comparing DCB with DES. In 13 trials, DCB was used with a bailout stent in case of flow-limiting dissection after DCB, with only 7.9% (99/1260) of patients requiring a bailout stent after DCB. In 11 trials, DCB was used in combination with a BMS. Of the 24 trials analyzed, eight were focused on SVD (baseline RVD ≤3 mm), six on MI, two on bifurcation lesions, and eight on unspecified de novo lesions as indications. A total of 3544 patients were included, 1773 assigned to DCB and 1771 assigned to DES. Most of the included studies utilized the SeQuent Please paclitaxel-coated balloon (15 of 24) and second-generation DESs (15 of 24).

    Fourteen RCTs provided outcome data comparing DCB with uncoated devices (12 with BMS and two with POBA). In six trials, DCBs were used with a bailout stent, and 5.2% (25/474) of patients required a BMS stent after DCB. In 11 trials, DCBs were used in combination with a BMS. Of the 14 trials analyzed, one was focused on SVD, four on MI, two on high bleeding risk, three on bifurcation lesions, and four on unspecified de novo lesions as indications. A total of 1699 patients were included, with 880 assigned to DCB and 819 assigned to uncoated devices. In the majority of the studies (9 out of 14), the SeQuent Please paclitaxel-coated balloon was used.

    Table 1 presents the detailed baseline information on trials, patients, follow-up, and intervention. Table 2 summarizes the baseline clinical and angiographic characteristics of the patients and lesions included in the analysis. There were no significant differences in the assessed variables between treatments, except for age (p<0.05). All RCTs were open-label trials due to the nature of the intervention. Nine trials were considered low quality with a Jadad score of 3 points, while the other 24 RCTs were of high quality with a Jadad score of 4-6 (Supplementary Table 1, only online).

    Table 1
    Baseline Characteristics of the Included Studies

    Table 2
    Baseline Characteristics of the Included Patients and Lesions

    Primary outcomes

    DCBs were associated with significantly lower rates of TLR (OR=0.48; 95% CI: 0.33, 0.70; p=0.01; I2=0%) (Fig. 2), MACE (OR=0.43; 95% CI: 0.30, 0.61; p<0.001; I2=7.8%) (Fig. 3), and LLL (WMD=-0.35; 95% CI: -0.53, -0.18; p<0.001; I2=90.7%) (Fig. 4) when compared with uncoated devices.

    Fig. 2
    Forest plot of target lesion revascularization comparing drug-coated balloons (DCB) with uncoated devices (A) and drug-eluting stents (DES) (B). *The complete list of references for the included studies is provided in Supplementary Material (only online). OR, odds ratio; CI, confidence interval.

    Fig. 3
    Forest plot of major adverse cardiac events comparing drug-coated balloons (DCB) with uncoated devices (A) and drug-eluting stents (DES) (B). *The complete list of references for the included studies is provided in Supplementary Material (only online). OR, odds ratio; CI, confidence interval.

    Fig. 4
    Forest plot of late lumen loss comparing drug-coated balloons (DCB) with uncoated devices (A) and drug-eluting stents (DES) (B). *The complete list of references for the included studies is provided in Supplementary Material (only online). WMD, weighted mean differences; CI, confidence interval.

    There were no significant differences between DCBs and DESs in terms of TLR (OR=1.34; 95% CI: 0.96, 1.85; p=0.370; I2=46.6%) (Fig. 2), MACE (OR=1.04; 95% CI: 0.83, 1.31; p=0.814; I2=42.9%) (Fig. 3), and LLL (WMD=0.04; 95% CI: -0.05, 0.12; p=0.429; I2=91.5%) (Fig. 4).

    Secondary angiographic outcomes

    DCBs was associated with higher MLD (WMD=0.33; 95% CI: 0.19, 0.48; p<0.001; I2=75.7%), lower DS (WMD=-9.13; 95% CI: -15.00, -3.26; p=0.002; I2=85.5%), and lower rates of binary restenosis (OR=0.30; 95% CI: 0.14, 0.65; p=0.002; I2=68.1%) when compared with uncoated devices (Table 3).

    Table 3
    Results of Secondary Angiographic and Clinical Outcomes

    DCB were associated with lower MLD (DCB: WMD=-0.25; 95% CI: -0.34, -0.15; p<0.001; I2=84.6%;), higher DS (DCB: WMD=6.87; 95% CI: 3.06, 10.68; p<0.001; I2=90.3%;), and higher rates of binary restenosis (OR=1.69; 95% CI: 1.12, 2.53; p=0.012; I2=34.5%) when compared with DES (Table 3).

    Secondary clinical outcomes

    DCB were associated with a lower incidence of TVR (OR=0.30; 95% CI: 0.12, 0.72; p=0.007; I2=0%) and lower all-cause mortality (OR=0.34; 95% CI: 0.15, 0.79; p=0.011; I2=0%), compared with uncoated devices (Table 3). There were no significant differences in terms of TVR, stent thrombosis, MI, cardiac death, and all-cause death between DCB and DES (Table 3).

    Long-term follow-up clinical outcomes

    Two RCTs comparing DCB with BMS evaluated follow-up outcomes of 18 months to 5 years. Meta-analysis results revealed no significant differences between DCB and BMS in terms of TLR, MACE, MI, and cardiac death (Table 4).

    Table 4
    Results of Long-Term Clinical Outcomes

    Six RCTs comparing DCB with DES provided follow-up outcomes of 18 months to 3 years. There were no significant differences between DCB and DES in terms of TLR, MACE, TVR, stent thrombosis, MI, cardiac death, and all-cause death (Table 4).

    Sensitivity analysis

    Leave-one-out sensitivity analysis was conducted on all outcomes. For DCB versus uncoated devices, inconsistent results were found in the incidences of TVR and MI. For DCB versus DES, sensitivity analysis indicated that no individual study significantly altered any of the primary and secondary outcomes.

    Subgroup analysis

    For DCB versus uncoated devices, subgroup analysis was conducted based on whether DCB was used with a bailout or systematic BMS. Most of the subgroup analysis results were consistent with the overall results, except that significantly less binary restenosis and MI were found only in the subgroup of DCB+ bailout BMS (Supplementary Table 2, only online).

    For DCB versus DES, subgroup analysis was conducted based on clinical indications (SVD, MI, bifurcation, and unspecified de novo), whether DCB was used with a bailout or systematic BMS, and types of DES used (first-generation and second-generation). Most of the subgroup analysis results were consistent with the overall results. In subgroup analysis of SVD indication, less LLL was found in the DCB group, compared with DES group, while no significant difference was found between groups in terms of DS and binary restenosis (Supplementary Table 3, only online).

    In subgroup analysis of bailout or systematic BMS, greater LLL was found in DCB+systematic BMS, compared with DES groups, while less LLL was found in DCB+bailout BMS, compared with DES groups. Meta-regression analysis showed that the between-subgroups association was significant (p=0.001) (Supplementary Table 3, only online). A higher incidence of binary restenosis was found for DCB+systematic BMS, compared with DES groups, while no significant difference was found comparing DCB+bailout BMS with DES (Supplementary Table 3, only online).

    There was no significant difference between DCB and first-generation DES groups in terms of DS and incidence of binary restenosis, while higher DS and binary restenosis rates were found in DCB, compared with second-generation DES groups (Supplementary Table 3, only online).

    Publication bias

    Publication bias was assessed for primary outcomes using Begg’s test and Egger’s test. For TLR (Egger’s test p=0.007) and LLL (Egger’s test p=0.007) comparing DCB with BMS, the results showed the presence of significant publication bias. However, the trim-and-fill method did not add any new studies, and the estimates did not change (Supplementary Table 4, only online).

    For LLL comparing DCB versus DES, result indicated the presence of significant publication bias (Egger’s test p=0.010). The trim-and-fill analysis identified seven missing studies after four iterations using the Linear method. After adding the seven studies, significantly less LLL was found in the DCB group, compared with the DES group (WMD=-0.11; 95% CI: -0.20, -0.01; p=0.040), indicating that the pooled results were not robust and that more studies need to be included in this analysis to reduce publication bias (Supplementary Table 4, only online and Supplementary Fig. 1, only online). No significant publication bias was detected in other outcomes.

    DISCUSSION

    In recent years, the use of DCBs for de novo coronary lesions has become an area of active research, with several meta-analyses assessing its performance. However, some of these studies had limitations, such as comparing DCBs with the mixed data of DES and uncoated devices25, 26 or including both observational studies and RCTs.27, 28, 29 In this up-to-date meta-analysis, we included the largest sample size to date, comprising 33 RCTs and conducted separate analyses comparing DCB with uncoated devices and DES. Subgroup analysis was also performed based on difference clinical indications, whether DCB was used with a bailout or systematic BMS, and types of DES used to better evaluate the efficacy of DCB in different circumstances. Additionally, we assessed the long-term clinical impacts of DCB, with follow-up outcomes of 18 months to 5 years. We believe that our study provides a more comprehensive and throughout analysis of the roles of DCB in the treatment of de novo coronary lesions.

    Based on the current analysis, DCBs offered superior efficacy and safety over uncoated devices in treating de novo coronary lesions, as indicated by significantly improved clinical and angiographic outcomes in patients receiving DCB. Results of subgroup analyses suggested that DCB used with bailout BMSs had better effects in reducing binary restenosis and MI, compared with systematic BMSs. Although DESs remain the default treatment for patients undergoing PCI,30, 31 BMSs are still used in a small proportion of patients, especially those with high bleeding risk to minimize the duration of antiplatelet therapy. Two RCTs included in this analysis assessed patients at high bleeding risk, and both studies demonstrated better clinical and angiographic outcomes (lower TLV, MACE, and LLL) in patients treated with DCB+bailout BMS, compared to those with BMS alone.32, 33 Results of the present study suggested that DCB could be an alternative strategy with potential benefit for this subset of patients.

    Compared with DESs, DCBs showed inferior angiographic outcomes, with a lower MLD and higher LLL, DS, and binary restenosis. Nevertheless, these inferior angiographic results did not translate into worse clinical outcomes, with no significant differences between both treatments in terms of TLR, MACE, TVR, MI, stent thrombosis, cardiac death, and all-cause mortality. In addition, a major concern of DCB application is its unclarified long-term clinical impacts. Results of this meta-analysis demonstrated similar clinical outcomes between patients with DCB and those with DES at 18-month to 3-year follow-up. These findings suggest that DCB could be an effective alternative in the treatment of de novo coronary lesions.

    SVD are commonly associated with smaller caliber vessels and longer lesions, which increase the risk of ISR.34 DESs are known to cause neointimal hyperplasia and late occurrence of neoatherosclerosis and stent thrombosis, which can be more pronounced in small vessels with limited space to accommodate the neointima.35 Therefore, the efficacy of DESs in treating SVD has been proposed to be restricted as it leads to LLL, which can result in late ISR.36 Interestingly, in subgroup analysis of SVD, DCBs showed similar TLR and MACE rates and lower LLL, compared to DESs. The results were consistent even when analyses were further limited to compare DCB with second-generation DES. Thus, DCB might be a promising alternative for the treatment for SVD.

    While the efficacy of DCB plus systematic BMS has not been proven superior to DES, several trials have shown that DCBs used with a bailout BMS may provide better results.19, 37, 38 It has been suggested that avoiding permanent implants might prevent long-term complications associated with foreign metallic stents. However, others have argued that this might come at a price of early and late thrombotic complications.39 Results of our subgroup analysis showed that DCB+bailout BMS had non-inferior angiographic outcomes, while DCB+systematic BMS had inferior angiographic outcomes, compared with DES. Nevertheless, DCB+bailout BMS, as well as DCB+systematic BMS, showed 6- to 12-month clinical outcomes comparable to DESs. In the DCB+bailout BMS subgroup, only 7.9% (99/1260) of patients received a bailout stent. These findings provide evidence for the application of DCB as a standalone intervention or in combination with a BMS for managing de novo coronary lesions. Whether DCBs with a bailout stent could provide long-term clinical benefits require further investigation.

    Second-generation DESs have been shown to overcome the limitations of first-generation DES and to provide better clinical efficacy in treating de novo coronary artery lesions.40, 41 Results of our subgroup analyses indicates that DCBs are non-inferior to first-generation DESs and second-generation DESs in terms of TLR, MACE, and LLL, further supporting the use of DCB.

    There are several limitations to our meta-analysis. First, the use of different brands of DCBs and DESs, variations in core laboratory assessments of angiographic outcomes, and differences in the definitions of clinical endpoints across the trials may have contributed to the observed heterogeneity. While we conducted sensitivity and subgroup analyses to explore the influence of certain factors (such as indications and second-generation DESs) on heterogeneity and overall effect size, the small sample size prevented the assessment of other factors. Moreover, the majority of the included studies had a limited follow-up duration of 6 to 12 months, with only eight RCTs providing follow-up data of 18 months to 5 years, which is insufficient to demonstrate the long-term safety of DCB. Finally, patient-level data were not available, which limited our ability to adjust for patient-level confounders or to perform patient-level sensitivity analyses to identify which patient and lesion characteristics would derive the greatest benefit from DCB treatment.

    In conclusion, this meta-analysis demonstrated that DCB is associated with favorable angiographic and clinical outcomes when compared to uncoated devices (BMS and POBA) in the treatment of de novo coronary lesions. While DCB showed inferior angiographic outcomes when compared to DES, the clinical outcomes were similar. The clinical efficacy of DCB was consistent across different indications and was maintained when DCB was used with either a systematic or bailout stent, as well as when compared to second-generation DESs. The long-term clinical efficacy of DCBs remains unclear and warrants further investigation.

    SUPPLEMENTARY MATERIALS

    SUPPLEMENTARY MATERIAL

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    Supplementary Table 1

    Quality Assessment Results Jadad Scale for Reporting Randomized Controlled Trials

    Click here to view.(36K, pdf)

    Supplementary Table 2

    Result of Subgroup Analysis Using Data of DCB vs. BMS

    Click here to view.(37K, pdf)

    Supplementary Table 3

    Result of Subgroup Analysis Using Data of DCB vs. DES

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    Supplementary Table 4

    Results of Publication Bias and Trim-and-Fill Analyses

    Click here to view.(30K, pdf)

    Supplementary Fig. 1

    Trim-and-fill analysis of late lumen loss comparing drug-coated balloon with drug-eluting stents.

    Click here to view.(36K, pdf)

    Notes

    The authors have no potential conflicts of interest to disclose.

    ETHICAL APPROVAL:This article does not comprise any data obtained through experiments with human participants or animals performed by any of the authors.

    AUTHOR CONTRIBUTIONS:

    • Conceptualization: Dejin Wang.

    • Data curation: Xiqian Wang, Tianxiao Yang, and Hongliang Tian.

    • Formal analysis: Dejin Wang, Xiqian Wang, and Yuanzhen Su.

    • Investigation: Dejin Wang, Xiqian Wang, and Tianxiao Yang.

    • Methodology: Dejin Wang and Xiqian Wang.

    • Project administration: Dejin Wang and Xiqian Wang.

    • Resources: Dejin Wang and Xiqian Wang.

    • Software: Xiqian Wang, Tianxiao Yang, and Hongliang Tian.

    • Supervision: Dejin Wang.

    • Validation: Dejin Wang.

    • Visualization: Dejin Wang.

    • Writing—original draft: Dejin Wang.

    • Writing—review & editing: Qilei Wang.

    • Approval of final manuscript: all authors.

    AVAILABILITY OF DATA AND MATERIAL

    All data generated or analyzed during this study are included in this published article.

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    MeSH Terms
    Coronary Artery Disease
    Coronary Vessels*
    Drug-Eluting Stents
    Incidence
    Metals
    Myocardial Infarction
    Stents
    Treatment Outcome
    Metrics
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