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Comparing the efficacy and safety of two different drug-coated balloons in in-stent restenosis: Two-year clinical outcomes of the RESTORE ISR China randomized trial

Published:September 23, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.08.014

      Highlights

      • Drug-coated balloon (DCB) angioplasty is a promising treatment for in-stent restenosis.
      • Identification of SeQuent® Please DCB has sustained safety and efficacy.
      • Restore DCB has similar clinical outcomes comparing to the SeQuent® Please DCB.
      • The result of quantitative flow ratio did show non-inferior outcomes for one explicit treatment bunch.
      • Restore DCB sustained clinical safety and efficacy at 24-month follow up.

      Abstract

      Background

      This head-to-head, multicenter, randomized trial investigated the safety and efficacy of Restore (Cardionovum, Bonn, Germany) drug-coated balloon (DCB) angioplasty in an Asian patient population with coronary drug-eluting stent in-stent restenosis (DES-ISR).

      Methods

      A total of 240 patients with coronary DES-ISR were treated with Restore DCB or with SeQuent® Please (Braun, Melsungen, Germany) DCB. This trial used nine-month in-segment late lumen loss (LL) as the primary endpoint. Secondary endpoints included two-year clinical event rates.

      Results

      Patient, lesion, and procedural characteristics in both treatment groups were similar. Nine-month in-segment LL was 0.38 ± 0.50 mm with Restore vs. 0.35 ± 0.47 mm with SeQuent® Please (p for non-inferiority = 0.02). The two-year follow-up rates were 95.8 % (115/120) in the Restore group and 94.2 % (113/120) in the SeQuent® Please group. Both groups had similar one- and two-year target lesion failure (TLF) rates (13.3 % vs. 12.6 %; p = 0.87 at one year, 14.8 % vs. 15.0 %; p = 1.0 at two years). Moreover, the all-cause mortality and myocardial infarction rates were 0 and 3.5 % (4/120) in the Restore group and 0.9 % (1/120) and 3.5 % (4/120) in the SeQuent® Please group, respectively. Additional analyzing of vessel quantitative flow ratio (QFR) did also show noninferior outcomes for one explicit treatment bunch.

      Conclusions

      The two-year follow-up indicated sustained long-term clinical safety and efficacy for both devices on the basis of QFR value.

      Graphical abstract

      Keywords

      Introduction

      Even though the development of drug-eluting stents (DESs) has increased anti-restenotic performance, in-stent restenosis (ISR) remains the primary cause of percutaneous coronary intervention failure [
      • Yerasi C.
      • Case B.C.
      • Forrestal B.J.
      • Torguson R.
      • Weintraub W.S.
      • Garcia-Garcia H.M.
      • et al.
      Drug-coated balloon for de novo coronary artery disease: JACC state-of-the-art review.
      ]. Mounting evidence on drug-coated balloon (DCB) angioplasty and repeat stenting with DES has identified them as the most promising treatments for ISR. Both strategies are used based on a Class I indication to treat ISR according to the European Society of Cardiology guidelines [
      • Neumann F.J.
      • Sousa-Uva M.
      • Ahlsson A.
      • Alfonso F.
      • Banning A.P.
      • Benedetto U.
      • et al.
      2018 ESC/EACTS Guidelines on myocardial revascularization.
      ,
      • Giacoppo D.
      • Gargiulo G.
      • Aruta P.
      • Capranzano P.
      • Tamburino C.
      • Capodanno D.
      Treatment strategies for coronary in-stent restenosis: systematic review and hierarchical Bayesian network meta-analysis of 24 randomised trials and 4880 patients.
      ]. The PEPCAD China ISR trial was designed to investigate the safety and efficacy of paclitaxel-coated balloon (PCB) use compared to paclitaxel-eluting stent (PES) placement with regard to meeting the Chinese regulatory requirements for the approval of investigational PCB use [
      • Xu B.
      • Gao R.
      • Wang J.
      • Yang Y.
      • Chen S.
      • Liu B.
      • et al.
      A prospective, multicenter, randomized trial of paclitaxel-coated balloon versus paclitaxel-eluting stent for the treatment of drug-eluting stent in-stent restenosis: results from the PEPCAD China ISR trial.
      ,
      • Xu B.
      • Qian J.
      • Ge J.
      • Wang J.
      • Chen F.
      • Chen J.
      • et al.
      Two-year results and subgroup analyses of the PEPCAD China in-stent restenosis trial: a prospective, multicenter, randomized trial for the treatment of drug-eluting stent in-stent restenosis.
      ]. Additionally, the recently published three-year follow-up results of the BASKET-SMALL 2 study published by Jeger et al., which were consistent with the results of the PEPCAD China ISR trial [
      • Jeger R.V.
      • Farah A.
      • Ohlow M.A.
      • Mangner N.
      • Mobius-Winkler S.
      • Weilenmann D.
      • et al.
      Long-term efficacy and safety of drug-coated balloons versus drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial.
      ]. Other studies have revealed significant angiographic and clinical benefits of DCB treatment compared to plain old balloon angioplasty and different types of DCBs [
      • Rittger H.
      • Waliszewski M.
      • Brachmann J.
      • Hohenforst-Schmidt W.
      • Ohlow M.
      • Brugger A.
      • et al.
      Long-term outcomes after treatment with a paclitaxel-coated balloon versus balloon angioplasty: insights from the PEPCAD-DES Study (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel-Coated Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter).
      ,
      • Lee J.M.
      • Park J.
      • Kang J.
      • Jeon K.H.
      • Jung J.H.
      • Lee S.E.
      • et al.
      Comparison among drug-eluting balloon, drug-eluting stent, and plain balloon angioplasty for the treatment of in-stent restenosis: a network meta-analysis of 11 randomized, controlled trials.
      ,
      • Briguori C.
      • Visconti G.
      • Golino M.
      • Focaccio A.
      • Scarpelli M.
      • Nuzzo S.
      • et al.
      Paclitexel versus sirolimus-coated balloon in the treatment of coronary instent restenosis.
      ].
      SeQuent® Please (Braun, Melsungen, Germany) is an iopromide-based DCB that is coated with 3 mg paclitaxel/mm2 of balloon surface and uses iopromide as a hydrophilic excipient, which has been proved to be an alternative to percutaneous therapies for ISR [
      • Xu B.
      • Gao R.
      • Wang J.
      • Yang Y.
      • Chen S.
      • Liu B.
      • et al.
      A prospective, multicenter, randomized trial of paclitaxel-coated balloon versus paclitaxel-eluting stent for the treatment of drug-eluting stent in-stent restenosis: results from the PEPCAD China ISR trial.
      ,
      • Xu B.
      • Qian J.
      • Ge J.
      • Wang J.
      • Chen F.
      • Chen J.
      • et al.
      Two-year results and subgroup analyses of the PEPCAD China in-stent restenosis trial: a prospective, multicenter, randomized trial for the treatment of drug-eluting stent in-stent restenosis.
      ,
      • Rittger H.
      • Waliszewski M.
      • Brachmann J.
      • Hohenforst-Schmidt W.
      • Ohlow M.
      • Brugger A.
      • et al.
      Long-term outcomes after treatment with a paclitaxel-coated balloon versus balloon angioplasty: insights from the PEPCAD-DES Study (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel-Coated Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter).
      ,
      • Xia C.
      • Jiang Y.
      • Li S.
      • Xiong D.
      • Chen X.
      • Chen Y.
      In vitro and in vivo comparative evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device.
      ]. Restore (Cardionovum, Bonn, Germany) is coated with 3 mg paclitaxel/mm2 of balloon surface but uses shellac-ammonium salt as an excipient. Paclitaxel has been considered as a promising drug for local application to prevent restenosis without showing cytotoxic effects after percutaneous transluminal coronary angioplasty, shellac-ammonium salt drug coating technology to provide a targeted paclitaxel release in vessel lumen has been published regarding the safety and efficacy of excipient [
      • Briguori C.
      • Visconti G.
      • Golino M.
      • Focaccio A.
      • Scarpelli M.
      • Nuzzo S.
      • et al.
      Paclitexel versus sirolimus-coated balloon in the treatment of coronary instent restenosis.
      ,
      • Xia C.
      • Jiang Y.
      • Li S.
      • Xiong D.
      • Chen X.
      • Chen Y.
      In vitro and in vivo comparative evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device.
      ,
      • Axel D.I.
      • Kunert W.
      • Goggelmann C.
      • Oberhoff M.
      • Herdeg C.
      • Kuttner A.
      • et al.
      Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery.
      ]. A previous study was designed to compare the characteristics and performance of a novel DCB to a benchmark device (Restore vs. SeQuent® Please) that demonstrated Restore DCB was better in preclinical environment [
      • Xia C.
      • Jiang Y.
      • Li S.
      • Xiong D.
      • Chen X.
      • Chen Y.
      In vitro and in vivo comparative evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device.
      ]. However, it was not feasible to make conclusions regarding the efficacy and safety of the Restore DCB as a clinical treatment in a mimicked ISR setting [
      • Xia C.
      • Jiang Y.
      • Li S.
      • Xiong D.
      • Chen X.
      • Chen Y.
      In vitro and in vivo comparative evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device.
      ]. Therefore, we prospectively performed a randomized study comparing angiographic and clinical outcomes among different types of DCBs for patients with coronary ISR [
      • Chen Y.
      • Gao L.
      • Qin Q.
      • Chen S.
      • Zhang J.
      • Chen H.
      • et al.
      Comparison of 2 different drug-coated balloons in in-stent restenosis: the RESTORE ISR China Randomized Trial.
      ]. The nine-month angiographic findings and 12-month clinical results of the RESTORE ISR China randomized trial used in this study were previously published [
      • Chen Y.
      • Gao L.
      • Qin Q.
      • Chen S.
      • Zhang J.
      • Chen H.
      • et al.
      Comparison of 2 different drug-coated balloons in in-stent restenosis: the RESTORE ISR China Randomized Trial.
      ]. The principal result was that the in-segment lumen loss (LL) was not different between the Restore DCB and SeQuent® Please DCB (0.38 ± 0.50 mm vs. 0.35 ± 0.47 mm, p for non-inferiority = 0.02), and both groups had similar 12-month clinical outcomes. In the present study, we report on not only the 24-month outcomes, but also vessel quantitative flow ratio (QFR) at baseline, QFR at nine months, and delta QFR as supplements aimed to evaluate the long-term clinical safety and effectiveness of the Restore DCB in China.

      Methods

      Study design

      The RESTORE ISR China was a randomized (1:1), head-to-head, multicenter trial in a Chinese population that recruited a total of 240 patients with coronary ISR who were treated with Restore DCB or with SeQuent® Please DCB. Patient, lesion, and procedural characteristics in both DCB groups were similar. The study design, study device, as well as baseline patient and procedure characteristics were previously described [
      • Chen Y.
      • Gao L.
      • Qin Q.
      • Chen S.
      • Zhang J.
      • Chen H.
      • et al.
      Comparison of 2 different drug-coated balloons in in-stent restenosis: the RESTORE ISR China Randomized Trial.
      ] (Table 1 and Fig. 1). Moreover, the QFR of vessels from patients (AngioPlus, Pulse medical imaging technology Co., Ltd., Shanghai, China) were calculated at baseline, at nine months after DCBs angioplasty, and the difference between baseline and nine months [
      • Tu S.
      • Westra J.
      • Yang J.
      • von Birgelen C.
      • Ferrara A.
      • Pellicano M.
      • et al.
      Diagnostic accuracy of fast computational approaches to derive fractional flow reserve from diagnostic coronary angiography: the International Multicenter FAVOR Pilot Study.
      ,
      • Asano T.
      • Katagiri Y.
      • Collet C.
      • Tenekecioglu E.
      • Miyazaki Y.
      • Sotomi Y.
      • et al.
      Functional comparison between the BuMA Supreme biodegradable polymer sirolimus-eluting stent and a durable polymer zotarolimus-eluting coronary stent using quantitative flow ratio: PIONEER QFR substudy.
      ].
      Table 1Baseline patient and lesion characteristics (intention-to-treat population).
      Restore DCB group (n = 120)SeQuent Please DCB group (n = 120)p-Value
      Age, years63.6 ± 8.763.9 ± 9.30.81
      Male77.5 (93)75.0 (90)0.65
      BMI, kg/m225.7 ± 3.026.1 ± 3.40.28
      Diabetes mellitus38.3 (46)38.3 (46)1.00
      Insulin-treated diabetes18.3 (22)16.7 (20)0.73
      Hypertension63.3 (76)70.8 (85)0.22
      Hyperlipidemia43.3 (52)40.8 (49)0.69
      Smoking24.2 (29)28.3(34)0.46
      Previous MI42.5 (51)40.0 (48)0.69
      Previous CABG0.8 (1)0.8 (1)1.00
      Previous stroke17.5 (21)11.7(14)0.20
      Family history of CAD24.2 (29)18.3(22)0.27
      Unstable angina74.2 (89)78.3 (94)0.45
      LVEF, %60.5 ± 8.8 (111)60.9 ± 7.8 (91)0.75
      Multivessel disease17.5 (21)23.3 (28)0.26
      Target vessel location
       LAD37.7 (49)52.3 (69)0.02
       D3.1 (4)2.3 (3)0.72
       LCX15.4 (20)13.6 (18)0.69
       OM0.8 (1)1.5 (2)1.00
       RCA38.5 (50)29.5 (39)0.13
       PDA/PL4.6 (6)0.8 (1)0.07
      Number of nontarget lesions1.13 ± 0.341.14 ± 0.420.94
       116.7 (20)26.7 (32)0.06
       22.5 (3)2.5 (3)1.00
       30 (0)0.8 (1)1.00
      Mehran type
       I59.2 (77)60.6 (80)0.82
       II30.8 (40)27.3 (36)0.53
       III10.0 (13)12.1(16)0.58
       IV0 (0)0 (0)
      Stent type related to ISR
       BMS2.3 (3)0.8 (1)0.37
       DES97.7 (127)99.2 (131)0.37
      Values are mean ± SD or % (n).
      BMI, body mass index; BMS, bare-metal stent; CABG, coronary artery bypass grafting; CAD, coronary artery disease; D, diagonal branch; DCB, drug-coated balloon; DES, drug-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; LVEF, left ventricular ejection fraction; ISR, in-stent restenosis; MI, myocardial infarction; OM, obtuse marginal branch; PDA, posterior descending artery; PL, posterolateral; RCA, right coronary artery.
      Fig. 1
      Fig. 1Patient flow chart.
      The as-treated set consisted of subjects who received only study devices at target lesions.
      DCB, drug-coated balloon; ITT, intention-to-treat.
      The in-segment LL at nine months was chosen as the primary endpoint. Main secondary endpoints included rates of acute success (for device, lesions, and procedure) and nine-month binary restenosis (>50 % diameter stenosis). Furthermore, secondary endpoints included the rates of target lesion failure (TLF) at 1, 6, 9, 12, and 24 months. In addition, TLF was defined as a composite of cardiac death, target vessel myocardial infarction (TV-MI), and ischemia-driven target lesion revascularization (TLR). TLR was defined as any repeat revascularization of the original target lesion site that occurred 30 or more days after the index procedure and was driven by clinical findings (presence of ischemic symptoms and/or a positive functional ischemia study), in the presence of a diameter stenosis (DS) ≥50 % as determined by the angiographic core laboratory. Revascularization without any ischemic symptoms or a positive functional ischemia for a DS ≥ 70 % was also considered to be clinically driven. Also, TLR was considered to be the area covered by the stent plus a 5-mm margin proximal and distal to the stent edges. Target vessel revascularization (TVR) was defined as any repeat revascularization of the target lesion or any segment of the epicardial coronary artery containing the target lesion or more proximal vessels. Criteria for clinically driven indication and clinical restenosis were the same as for TLR. Moreover, patient-oriented composite endpoint (PoCE) was chosen as another secondary endpoint, which was defined as a composite of all-cause death, all MI events, and any revascularization. The study was performed in accordance with the Helsinki Declaration. All participants provided written informed consent before randomization.

      Statistical planning and analyses

      The statistical analysis was performed at the Medical Statistics Department of the National Center for Cardiovascular Diseases (Beijing, China). All statistical analyses followed the intention-to-treat (ITT) principles. The as-treated set (ATS) was also used for sensitivity analysis. Continuous variables were presented as the means ± SD and compared using the Student's t-test. Categorical variables were presented as counts and percentages and compared using the chi-square test or Fisher's exact test when applicable. The cumulative incidence of clinical events was estimated with the Kaplan–Meier method and compared using the log-rank test. The value of 0.05 was used for all significance levels. R Studio 3.5.2 (R Foundation for statistical Computing, Vienna, Austria) was used for all statistical analyses.

      Results

      A total of 240 patients were treated with either Restore DCB or SeQuent® Please DCB. Baseline clinical and angiographic characteristics between the two groups were generally balanced for both the ITT and ATS populations, as previously reported (Table 1). Specifically, nine-month angiographic results have demonstrated that a Restore DCB strategy for in-segment LL in treating coronary ISR was non-inferior to SeQuent® Please DCB (0.38 ± 0.50 mm vs. 0.35 ± 0.47 mm, p for non-inferiority = 0.02) [
      • Chen Y.
      • Gao L.
      • Qin Q.
      • Chen S.
      • Zhang J.
      • Chen H.
      • et al.
      Comparison of 2 different drug-coated balloons in in-stent restenosis: the RESTORE ISR China Randomized Trial.
      ]. The 24-month follow-up rates were 95.8 % (115/120) in the Restore DCB group and 94.2 % (113/120) in the SeQuent® Please DCB group (Fig. 1).
      In the ITT analysis, the two groups had similar rates of major adverse cardiac events (MACEs) compared to the SeQuent® Please DCB group (Table 2). That is, rates of all-cause mortality and MI were 0 and 3.5 % (4/120) in the Restore group and 0.9 % (1/120) and 3.5 % (4/120) in the SeQuent® Please group at 24 months, respectively. None of these results were significantly statistically different. TVR at 24 months was significantly higher in the Restore DCB-treated patients (27 % vs. 15 %; p = 0.04). Furthermore, results were similar at 6, 9, and 12 months based on the statistical models (Table 3). The TLF rates at 24 months were 14.8 % (17/115) in the Restore DCB group and 15 % (17/113) in the SeQuent® Please DCB group (p = 1; Table 3), which were similar to the one-month (0.8 % vs. 0.8 %; p = 1), six-month (2.5 % vs. 4.2 %; p = 0.72), nine-month (11.7 % vs. 11.8 %; p = 0.98), and 12-month (13.3 % vs. 12.6 %; p = 0.87) results. Moreover, PoCEs were not different among patients who received the Restore DCB or those who received the SeQuent® Please DCB to treat DES-ISR lesions (31.3 % vs. 21.9 %; p = 0.27; Fig. 2). Analogously, the corresponding Kaplan–Meier analysis (Fig. 2, Fig. 3) did not identify any differences in the cumulative incidence of event rates (all-cause death, TV-MI, TLF, TLR, and PoCE) in the ITT analysis.
      Table 2Clinical outcomes after 24 months (intention-to-treat population).
      Restore DCB groupSeQuent® Please DCB groupDifference (95 % CI)p-Value
      1-monthn = 120n = 120
       All-cause death0 (0)0 (0)
       MI0.8 (1)0.8 (1)0 (−2.3, 2.3)1.00
       TLF0.8 (1)0.8 (1)0 (−2.3, 2.3)1.00
       TLR0 (0)0 (0)
       TVR0.8 (1)0 (0)0.8 (−0.8, 2.5)1.00
       PoCE1.7 (2)0.8 (1)0.9 (−2.0, 3.6)0.72
      12-monthn = 120n = 119
       All-cause death0 (0)0 (0)
       MI2.5 (3)3.4 (4)−0.9 (−5.1, 3.4)0.72
       TLF12.3 (16)12.6 (15)0.7 (−7.8, 9.3)0.87
       TLR13.3 (16)11.8 (14)1.6 (−6.8, 10.0)0.71
       TVR23.3 (28)12.6 (15)10.7 (1.1, 20.4)0.03
       PoCE29.2 (35)19.3 (23)9.8 (−0.95, 20.63)0.08
      24-monthn = 115n = 113
       All-cause death0 (0)0.9 (1)−1.8 (−2.6, 0.8)0.50
       MI3.5 (4)3.5 (4)0 (−4.8, 4.7)0.98
       TLF14.8 (17)15.0 (17)−0.2 (−9.5, 9.0)1.00
       TLR14.8 (17)14.2 (16)0.6 (−8.5, 9.8)1.00
       TVR27.0 (31)15.0 (17)11.9 (1.5, 22.4)0.04
       PoCE31.3 (36)23.9 (27)7.4 (−4 0.2, 19.0)0.27
      Note: Values are % (n). TLF was defined as a composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization. PoCE was defined as a composite of all-cause death, all MI events, and any revascularization.
      CI, confidence interval; DCB, drug-coated balloon; MI, myocardial infarction; PoCE, patient-oriented composite endpoint; TLF, target lesion failure; TLR, target lesion revascularization; TVR, target vessel revascularization.
      Table 3TVR and TLF after 24 months (intention-to-treat population).
      TVR/TLFRestore DCB groupSeQuent® Please DCB groupp-ValueDifference (95%CI)
      1-month
      n120120
      TVR0.8 (1)0 (0)1.000.8 (−2.3, 2.3)
      TLF0.8 (1)0.8 (1)1.00
      6-month
      n120120
      TVR5.8 (7)3.3 (4)0.352.5 (−2.8, 7.8)
      TLF2.5 (3)4.2 (5)0.72−1.7 (−6.2, 2.9)
      9-month
      n120119
      TVR20.8 (25)11.8 (14)0.069.1 (−0.2, 18.4)
      TLF11.7 (14)11.8 (14)0.98−0.1 (−8.2, 8.1)
      12-month
      n120119
      TVR23.3 (28)12.6 (15)0.0310.7 (−0.03, 21.4)
      TLF13.3 (16)12.6 (15)0.870.7 (−7.8, 9.2)
      24-month
      n115113
      TVR27.0 (31)15.0 (17)0.0411.9 (1.5, 22.4)
      TLF14.8 (17)15.0 (17)1.00−0.2 (−9.5, 9.0)
      Note: Values are % (n).
      TLF, target lesion failure; TVR, target vessel revascularization.
      Fig. 2
      Fig. 2Kaplan-Meier cumulative event curves for PoCE at 24-month follow-up.
      PoCE, patient-oriented composite endpoint.
      Fig. 3
      Fig. 3Kaplan-Meier cumulative event curves for individual components at 24-month follow-up.
      (A) Events are all-cause death; (B) myocardial infarction; (C) ischemia-driven target lesion revascularization; (D) target lesion failure.
      CI, confidence interval; HR, hazard ratio.
      Furthermore, there was additional analyzing of QFR value at baseline, QFR value at nine months, and delta QFR (QFR step-up in the lesion segment) of all 227 vessels. Angiographic results value at baseline have shown that Restore DCB was non-inferior to SeQuent® Please DCB (0.68 ± 0.18 vs. 0.68 ± 0.17; p = 0.788; Fig. 4A ). Consistently, recurrent restenosis target vessels QFR (49/227) value at baseline were 0.56 ± 0.17 in the Restore DCB group and 0.66 ± 0.20 in the SeQuent® Please DCB group (p = 0.080; Fig. 4B). Non-recurrent restenosis target vessels QFR (178/227) value at baseline were 0.72 ± 0.16 in the Restore DCB group and 0.69 ± 0.18 in the SeQuent® Please DCB group (p = 0.210; Fig. 4C). None of these results were significantly statistically different. Notably, compared to the SeQuent® Please DCB group, all vessels QFR (227) at nine months was significantly lower in the Restore DCB group (0.95 ± 0.04 vs. 0.93 ± 0.07; p = 0.005; Fig. 4D). Similarly, recurrent restenosis target vessels QFR (49/227) at nine months were significantly different between the two group (Restore DCB: 0.87 ± 0.09 vs. SeQuent® Please DCB: 0.92 ± 0.05; p = 0.028; Fig. 4E). Indeed, non-recurrent restenosis target vessels QFR (178/227) did not differ between Restore and SeQuent® Please group (Restore DCB: 0.96 ± 0.04 vs. SeQuent® Please DCB: 0.97 ± 0.04; p = 0.087; Fig. 4F). Finally, delta QFR of 227 vessels were computed, there were no differences in the Restore DCB group (227 vessels: 0.25 ± 0.16; 49 vessels: 0.30 ± 0.17; 178 vessels: 0.23 ± 0.15) compared to SeQuent® Please DCB group (227 vessels: 0.28 ± 0.17, p = 0.430; 49 vessels: 0.26 ± 0.15, p = 0.430; 178 vessels: 0.28 ± 0.18, p = 0.335). The cumulative frequency distribution curves of QFR are shown in Fig. 4G, H, and I.
      Fig. 4
      Fig. 4Cumulative frequency distribution curves of QFR.
      Note: Values are means ± SD. Group: Restore DCB (red) and SeQuent® Please (blue).
      (A) QFR at baseline (227 vessels); (B) QFR at baseline (49 vessels); (C) QFR at baseline (178 vessels); (D) QFR at nine-month (227 vessels); (E) QFR at nine months (49 vessels); (F) QFR at nine months (178 vessels); (G) Delta QFR (227 vessels); (H) Delta QFR (49 vessels); (I) Delta QFR (178 vessels).
      DCB, drug-coated balloon; QFR, quantitative flow ratio.

      Discussion

      Clinical results at 24 months

      The efficacy and safety of different DCB types for patients with coronary ISR have been extensively studied [
      • Yerasi C.
      • Case B.C.
      • Forrestal B.J.
      • Torguson R.
      • Weintraub W.S.
      • Garcia-Garcia H.M.
      • et al.
      Drug-coated balloon for de novo coronary artery disease: JACC state-of-the-art review.
      ,
      • Jeger R.V.
      • Farah A.
      • Ohlow M.A.
      • Mangner N.
      • Mobius-Winkler S.
      • Weilenmann D.
      • et al.
      Long-term efficacy and safety of drug-coated balloons versus drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial.
      ]. Research has shown that Restore DCB provided an advantage in drug delivery efficacy, and that it can avoid drug washing off and the potential risk for microembolization during catheter delivery to the target lesion site. However, further clinical studies on ISR are necessary in order to obtain the approval for the new device in China [
      • Xia C.
      • Jiang Y.
      • Li S.
      • Xiong D.
      • Chen X.
      • Chen Y.
      In vitro and in vivo comparative evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device.
      ].
      Some animal experiments and clinical trials confirmed that the Restore DCB group was non-inferior compared to the SeQuent Please DCB group. Animal research has shown that the mean injury score between the Restore group and SeQuent® Please group (0.78 ± 0.51 vs. 0.78 ± 0.51, p = 0.999) and the drug wash-off rate of the Restore group were substantially lower than those in the SeQuent® Please group (7 % ± 6 % vs. 51 % ± 9 %, p<0.001), which suggested that the Restore DCB might have lower complication rates [
      • Xia C.
      • Jiang Y.
      • Li S.
      • Xiong D.
      • Chen X.
      • Chen Y.
      In vitro and in vivo comparative evaluation of a shellac-ammonium paclitaxel-coated balloon versus a benchmark device.
      ]. The present study discovered that the Restore DCB was non-inferior to the SeQuent Please DCB for the primary endpoint of nine-month in-segment LL. Both devices had similar 12-month clinical outcomes [
      • Chen Y.
      • Gao L.
      • Qin Q.
      • Chen S.
      • Zhang J.
      • Chen H.
      • et al.
      Comparison of 2 different drug-coated balloons in in-stent restenosis: the RESTORE ISR China Randomized Trial.
      ]. Consistently, the rates for TLF and PoCE were not different at 24 months among patients who received Restore DCB and those with SeQuent® Please delivery of paclitaxel to treat DES-ISR lesions. Importantly, the Restore DCB group was associated with lower rates of all-cause death and MI compared to the SeQuent® Please group (0 % and 3.5 % vs. 0.9 % and 3.5 %), which might add important insights to the available clinical evidence on treatment strategy for ISR. Nevertheless, a long-term clinical follow-up is also needed to reevaluate the data.
      A large-scale post-market surveillance registry by Briguori et al., has indicated that 12-month TLF was not statistically and clinically different in DES-ISR patients treated with Restore DCB vs. sirolimus-coated balloon [15.5 % vs. 17 %, OR = 1.12 (0.65–1.95), p = 0.78], which was in agreement with the present TLF results [
      • Briguori C.
      • Visconti G.
      • Golino M.
      • Focaccio A.
      • Scarpelli M.
      • Nuzzo S.
      • et al.
      Paclitexel versus sirolimus-coated balloon in the treatment of coronary instent restenosis.
      ]. Interestingly, TVR rates in the Restore DCB group in the present study were higher than those in the SeQuent® Please group, with statistically significant difference between the two groups of patients at 9 (p = 0.06), 12 (p = 0.03), and 24 (p = 0.04) months. Importantly, TLR rates in both of these groups did not achieve statistical significance and remained at lower levels in the Restore DCB group compared to the SeQuent® Please group at 9 and 24 months, which was probably due to the residual effects of coronary heart disease. This remains an area of active research [
      • Rittger H.
      • Waliszewski M.
      • Brachmann J.
      • Hohenforst-Schmidt W.
      • Ohlow M.
      • Brugger A.
      • et al.
      Long-term outcomes after treatment with a paclitaxel-coated balloon versus balloon angioplasty: insights from the PEPCAD-DES Study (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel-Coated Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter).
      ,
      • Jeremias A.
      • Davies J.E.
      • Maehara A.
      • Matsumura M.
      • Schneider J.
      • Tang K.
      • et al.
      Blinded physiological assessment of residual ischemia after successful angiographic percutaneous coronary intervention: the DEFINE PCI Study.
      ]. A growing body of evidence supports the value of QFR to assess functional relevance of coronary stenoses [
      • Tu S.
      • Westra J.
      • Yang J.
      • von Birgelen C.
      • Ferrara A.
      • Pellicano M.
      • et al.
      Diagnostic accuracy of fast computational approaches to derive fractional flow reserve from diagnostic coronary angiography: the International Multicenter FAVOR Pilot Study.
      ]. Past studies have shown that 9-month follow-up QFR had the moderate predictive value for 24-month PoCE (area-under-the-curve: 0.83, 95 % CI: 0.65–1.00) [
      • Li L.
      • Guan C.
      • Meng S.
      • Bai Y.
      • Zhang Z.
      • Zou K.
      • et al.
      Short- and long-term functional results following drug-coated balloons versus drug- eluting stents in small coronary vessels: the RESTORE quantitative flow ratio study.
      ]. Our studies found all vessels QFR (227) and QFR of recurrent restenosis target vessels (49/227) after DCB were significantly different between the two groups of patients at nine months (p < 0.01). Indeed, compared to SeQuent Please DCB, all vessels QFR (227) at nine months were lower in the Restore DCB group, which supported the higher TVR rates in the Restore DCB group. Besides, based on the QFR of recurrent restenosis target vessels (49/227) at baseline, we found that Restore DCB group was associated with lower QFR at baseline compared to the SeQuent® Please group, which may be statistically meaningful. Furthermore, TVR rates were related to the number of diseased vessels, longer lesions, smaller reference vessel diameter, scheduled angiographic follow-up, and type of stent use [
      • Brener S.J.
      • Ertelt K.
      • Mehran R.
      • Genereux P.
      • Xu K.
      • Witzenbichler B.
      • et al.
      Predictors and impact of target vessel revascularization after stent implantation for acute ST-segment elevation myocardial infarction: lessons from HORIZONS-AMI.
      ]. We have discovered lesion length (OR: 1.08; 95 % CI: 1.01–1.15; p = 0.017), and vessel caliber lumen diameter (OR: 0.35; 95 % CI 0.13–0.89; p = 0.027) were independently associated with recurrent restenosis target vessels after DCB angioplasty, so which and past medical history of patients ought to be stratified by the QFRs of recurrent restenosis target vessels to look for more reasons of high rates of TVR in Restore DCB group [
      • Cai X.
      • Tian F.
      • Jing J.
      • Jin Q.
      • Zhou S.
      • Yin W.
      • et al.
      Prognostic value of quantitative flow ratio measured immediately after drug-coated balloon angioplasty for in-stent restenosis.
      ]. In addition, in order to strengthen the quality of this clinical trial, the underlying cause of the higher TVR rates in the Restore DCB group needs to be determined using intravascular imaging in a large-scale study. Future research should address the factors and mechanisms of ISR to provide further evidence for identifying its basic causes.

      Study limitations

      There are several limitations to this analysis. First, the study was powered for the primary endpoint, but was not sufficient to verify the differences in clinical endpoint events. Second, no clear-cut distinction of specific DES types was made for the present analyses. In fact, there was no evidence of different characteristics among DES types used to treat ISR in the clinical work. Third, detailed lesion morphological data obtained with intravascular imaging need to be ascertained, although it was not used in the present trial as it was not mandatory. Fourth, data pooling with other large-scale studies using Restore DCB might contribute to the statistical power in future analyses.

      Conclusions

      This prospective, head-to-head, multicenter, randomized trial showed that the new Restore DCB angioplasty remains safe and effective for up to 24 months based on vessel QFR. Moreover, during the prolonged 24-month clinical period, there was no significant difference in MACE and TLF rates in the Restore DCB group compared to the SeQuent® Please DCB group in Chinese patients with coronary ISR.

      Declaration of competing interest

      The authors declare that they have no competing interests.

      Acknowledgments

      The authors thank the patients who participated in the RESTORE ISR China trial and appreciate the dedicated efforts of the clinical research collaborators involved in this trial, and the contributions of the participating centers.

      Funding

      This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.

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