Author + information
- Received August 14, 2018
- Revision received September 9, 2018
- Accepted September 10, 2018
- Published online December 3, 2018.
- Yundai Chen, MDa,∗∗ (, )
- Lei Gao, MDa,∗,
- Qin Qin, MDb,
- Shaoliang Chen, MDc,
- Jun Zhang, MDd,
- Hui Chen, MDe,
- Lefeng Wang, MDf,
- Zening Jin, MDg,
- Yang Zheng, MDh,
- Zheng Zhang, MDi,
- Hui Li, MDj,
- Xue Li, MDk,
- Guosheng Fu, MDl,
- Lian Chen, MDa,
- Zhijun Sun, MDa,
- Yu Wang, MDa,
- Qinhua Jin, MDa,
- Feng Cao, MDa,
- Jun Guo, MDa,
- Yanyan Zhao, BSm,
- Changdong Guan, MScn,
- Wei Li, PhDm,
- Bo Xu, MBBSn,∗∗ (, )
- for the RESTORE ISR China Investigators
- aDepartment of Cardiology, Chinese PLA General Hospital, Beijing, China
- bDepartment of Cardiology, Tianjin Chest Hospital, Tianjin, China
- cDepartment of Cardiology, Nanjing First Hospital, Nanjing, China
- dDepartment of Cardiology, Cangzhou Central Hospital, Cangzhou, China
- eDepartment of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- fDepartment of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- gDepartment of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- hDepartment of Cardiology, The First Hospital of Jilin University, Jinlin, China
- iDepartment of Cardiology, The First Hospital of Lanzhou University, Lanzhou, China
- jDepartment of Cardiology, Daqing Oilfield General Hospital, Daqing, China
- kDepartment of Cardiology, Tangdu Hospital of the Fourth Military Medical University, Xi’an, China
- lDepartment of Cardiology, Sir Run Run Shaw, Zhejiang University School of Medicine, Zhejiang, China
- mMedical Research and Biometrics Center, National Center for Cardiovascular Diseases of China, Beijing, China
- nCatheterization Laboratories, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China
- ↵∗Address for correspondence:
Dr. Yundai Chen, Department of Cardiology, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China.
- ↵∗∗Dr. Bo Xu, Catheterization Laboratories, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, A 167, Beilishi Road, Xicheng District, Beijing 100037, China.
Objectives The aim of the present study was to evaluate the angiographic efficacy, clinical safety, and effectiveness of the Restore paclitaxel-coated balloon in a randomized trial designed to enable the approval of the new device in China.
Background Drug-coated balloon (DCB) angioplasty offers an effective treatment for in-stent restenosis. Restore is a new DCB with a SAFEPAX shellac-ammonium salt excipient that can avoid drug washing off during catheter delivery to the target lesion site.
Methods In the noninferiority RESTORE ISR China (Compare the Efficacy and Safety of RESTORE DEB and SeQuent Please in Chinese Patient With Coronary In-stent Restenosis) trial, eligible patients with first occurrence of drug-eluting stent ISR were randomized to the Restore DCB or SeQuent Please DCB in a 1:1 ratio stratified by diabetes. Angiographic and clinical follow-up was planned at 9 months and 1 year, respectively, in all patients. The study was powered for the primary endpoint of 9-month in-segment late loss.
Results Between May 2016 and July 2017, a total of 240 subjects at 12 sites were randomized to either the Restore group (n = 120) or the SeQuent Please group (n = 120). Nine-month in-segment late loss was 0.38 ± 0.50 mm with Restore versus 0.35 ± 0.47 mm with SeQuent Please; the 1-sided 97.5% upper confidence limit of the difference was 0.17 mm, achieving noninferiority of Restore compared with SeQuent Please (p for noninferiority = 0.02). Both DCBs had similar 1-year rates of target lesion failure (13.3% vs. 12.6%; p = 0.87).
Conclusions In this head-to-head randomized trial, the Restore DCB was noninferior to the SeQuent Please DCB for the primary endpoint of 9-month in-segment late loss. (Compare the Efficacy and Safety of RESTORE DEB and SeQuent Please in Chinese Patient With Coronary In-stent Restenosis; NCT02944890)
Drug-eluting stents (DES) have improved the clinical outcomes of patients with coronary artery disease by decreasing the risk for in-stent restenosis (ISR) compared with the bare-metal stents (1,2). However, ISR requiring repeat revascularization is still encountered in 5% to 10% of patients undergoing percutaneous coronary intervention (PCI) with DES. The optimal treatment for ISR remains an issue of clinical importance. Clinical trials have suggested that DES implantation and drug-coated balloon (DCB) angioplasty yield the most successful angiographic and clinical results, and both strategies are recommended for the treatment of ISR in the European clinical practice guidelines (Class I, Level of Evidence: A) (3).
The rationale for using DCBs derives from the notion that lipophilic drugs, such as paclitaxel, may be delivered to the vessel wall even with short balloon inflation times. This technology allows ISR treatment using drugs that inhibit neointimal proliferation without the implantation of a new stent. Most of the randomized studies comparing DCB to alternative percutaneous therapies for ISR treatment are based on the iopromide-based SeQuent Please DCB (Braun, Melsungen, Germany). However, alternative DCB devices are available for clinical applications. We found few prospective randomized studies comparing angiographic and clinical outcomes among different types of DCBs for patients with coronary ISR. The Restore paclitaxel-coated balloon (Cardionovum, Bonn, Germany) is a new-generation DCB with an innovative SAFEPAX shellac-ammonium salt excipient, which might avoid drug wash-off during catheter delivery to the target lesion site. With this study, we aimed to evaluate the angiographic efficacy and clinical safety and effectiveness of the Restore DCB in a randomized trial designed to enable the approval of the new device (with an ISR indication) in China.
Study design and population
RESTORE ISR China was a prospective, multicenter, randomized controlled trial comparing the Restore DCB with SeQuent Please in patients with ISR. The study protocol has been published (4). The protocol was approved by all ethics committees responsible for all participating centers. The major inclusion criteria were the following: age 18 to 80 years, coronary restenosis patterns Mehran types I to III, reference diameter 2.5 to 4.0 mm, and the presence of restenosis. Restenosis was defined as at least 70% diameter stenosis on visual assessment or at least 50% diameter stenosis on visual assessment with documented myocardial ischemia in-stent and/or <5 mm out of the stent. Excluded were patients with acute myocardial infarction ≤7 days before the procedure, more than 3 lesions requiring PCI treatment in the same artery, bifurcation with side branch diameters ≥2.5 mm, evidence of extensive thrombus in the target vessel, severe chronic heart failure or New York Heart Association functional class IV, severe valvular heart disease, stroke within 6 months before the procedure, and/or severe renal failure (glomerular filtration rate <30 ml/min).
Eligible patients who provided written informed consent were enrolled at 12 sites in China. We randomly stratified patients on the basis of lesion site and the presence or absence of diabetes mellitus. We used an interactive web response system to randomize patients, using a block size of 4 during the randomization procedure.
Study devices and procedures
The controlled device, SeQuent Please DCB, is an iopromide-based DCB that is coated with 3 μg paclitaxel/mm2 of balloon surface and uses iopromide as a hydrophilic excipient. The tested device, the Restore DCB, also is coated with 3 μg paclitaxel/mm2 of balloon surface but uses shellac-ammonium salt as an excipient, which might significantly reduce drug washing off during catheter delivery to the target lesion site (Online Appendix).
All patients received aspirin (either 100 mg/day for ≥3 days before PCI or a pre-PCI 300-mg loading dose) and clopidogrel (300 or 600 mg as a loading dose, followed by 75 mg/day) or ticagrelor (180 mg as a loading dose, followed by 90 mg twice daily) following clinical indications. During the procedures, we administered an initial bolus of 100 mg/kg unfractionated heparin, followed by additional boluses as necessary, or bivalirudin (bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure) to all patients. Pre-dilation was mandatory, but the technique for pre-dilation was at the operator’s discretion. After successful pre-dilation of the ISR lesion, patients were randomly assigned in a 1:1 ratio to treatment with either a Restore DCB or a SeQuent Please DCB. The DCB was inflated for 45 to 60 s at normal pressure, according to the morphological characteristics of the lesion (e.g., degree of calcification, length, tortuosity). After the operation, all patients, regardless of randomized treatment assignment, received at least 1 month of dual antiplatelet therapy followed by lifelong aspirin.
All patients were to be followed up at 1, 3, 6, 9, and 12 months, and angiographic follow-up was scheduled at 9 ± 1 month. We collected data using electronic clinical report forms during treatment at all investigational centers and completed data collection prospectively during hospital admission and follow-up. We used Web applications on the servers of the Center for Clinical Studies at Fuwai Hospital with DataTrack (5) (study management software) to capture the data. DataTrack meets all regulatory requirements. Patient files and other source data (particularly regarding informed consent, date of angiography, and outcomes) are kept for at least 10 years after the end of the study. Independent interventional cardiologists who were not participating in the study constituted the Clinical Events Committee (CEC). The CEC was charged with the development of specific criteria used for the categorization of clinical events and clinical endpoints in the study that were based on the protocol. The CEC met regularly to review and adjudicate all the clinical events with the required minimum data. All members of the CEC were blinded to the primary results of the trial. Unless a noncardiac cause was demonstrated, we considered deaths as cardiac. Diagnoses of myocardial infarction were made in accordance with the Society for Cardiovascular Angiography and Interventions definition of myocardial infarction (6). Case report forms clearly separated target lesions from target vessel revascularization (TVR). However, all angiograms of patients requiring TVR were analyzed at the core laboratory to confirm the exact revascularization site. We used the consensus report from the Bleeding Academic Research Consortium (7) to evaluate bleeding.
Quantitative coronary angiography
Trained and blinded personnel at the central core laboratory used standard methodologies to analyze all the angiograms. An automatic edge detection system (CAAS II System, Pie Medical Imaging, Maastricht, the Netherlands) was used for offline quantitative measurements. The Mehran and American College of Cardiology/American Heart Association angiographic classifications were used to assess lesion morphology (8,9). After intracoronary administration of nitroglycerin, the operator selected orthogonal views (3 separate projections avoiding vessel foreshortening and the overlap of major side branches) and repeated matched projections immediately after the intervention and at later follow-up. We performed quantitative analyses both in-lesion (narrowing size and references automatically identified by the system) and in-segment (lesion + complete treated segment + 5 mm adjacent margins). In addition, we measured reference vessel diameter, minimal luminal diameter [MLD], and percentage diameter stenosis before the procedure and at later follow-up. Finally, we determined acute luminal and net gain, late loss (LL), and binary restenosis rate (>50% diameter stenosis).
In-segment LL at 9 months was chosen as the primary endpoint. Main secondary endpoints included rates of acute success (for device, lesions, and procedure), 9-month binary restenosis (>50% diameter stenosis), target lesion failure (TLF), a patient-oriented composite endpoint, all-cause death, and myocardial infarction. TLF was defined as the composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization (Online Appendix).
The assumed mean in-segment LL was 0.46 ± 0.48 mm for the experimental and control groups. The noninferiority margin was 0.195 mm. The same margin was used in the SPIRIT III trial (10) and was even narrower than that in PEPCAD China ISR Trial (11). With a 1-sided 0.025 alpha level and a maximum 20% rate of loss to angiographic follow-up, randomizing 240 patients would provide 80% power to demonstrate noninferiority of the Restore DCB to SeQuent Please DCB.
All statistical analyses followed the intention-to-treat (ITT) principles. The as-treated set (ATS) was also used for sensitivity analysis. Continuous variables are presented as mean ± SD and categorical variables as counts and percentages. We used the Student’s t-test to compare normally distributed continuous variables. Chi-square or Fisher exact tests were used to compare categorical variables. We calculated the 95% confidence interval of the difference between 2 treatment arms using the normal approximation for continuous variables and the Wald asymptotic method for binary variables.
We conducted both lesion and patient-level analyses for 9-month in-segment LL. When analyzing the primary endpoint on a per subject basis, the average LL of 2 or more target lesions was calculated. For lesion-level analysis, generalized estimating equation were used to account for the cluster effect. One-year clinical follow-up was performed at 360 ± 30 days. We plotted time–to–first event curves using Kaplan-Meier estimates and compared them using the log-rank test. Cox regression was used to determine hazard ratios and corresponding 95% confidence intervals. All statistical analyses were performed at a 2-sided significance level of 0.05 using SAS version 9.4 (SAS Institute, Cary, North Carolina).
From May 2016 to July 2017, a total 240 patients with coronary ISR were randomly assigned to either the Restore DCB (n = 120) or the SeQuent Please DCB (n = 120) treatment group. Figure 1 shows the flowchart for the trial.
Baseline clinical and angiographic characteristics between the 2 groups were generally balanced for both ITT and ATS population (Table 1, Online Table S1). There were no significant differences in terms of target vessel distribution and Mehran classification, except for a higher frequency of left anterior descending coronary artery diseases in the SeQuent Please DCB arm (p = 0.02). The reference vessel diameters and lesion lengths relative to the operative and device characteristics were similar between the groups (Tables 2 and 3⇓⇓, Online Tables S2 and S3). Likewise, MLD and percentage diameter stenosis behaved similarly pre-procedure in both groups. Pre-dilation was used in all patients. No post-dilation or bail-out stenting was used after any of the treatments. Immediately after the procedure, MLD behaved similarly, whereas percentage stenosis was significantly higher in the Restore DCB treatment group (22.3 ± 13.3% vs. 16.8 ± 11.7%; p <0.001).
Angiographic follow-up data were available in 106 patients in the Restore DCB arm and 102 patients in the SeQuent Please DCB arm at 9 months. Nine-month in-segment LL in the ITT population on the basis of per patient analysis was 0.38 ± 0.50 mm for Restore and 0.35 ± 0.47 mm for SeQuent Please; the 1-sided 97.5% upper confidence limit of the difference was 0.17 mm, achieving noninferiority of Restore compared with SeQuent Please (p for noninferiority = 0.02). Noninferiority also was met on the basis of the lesion level or in the ATS analysis (Table 4). In addition, there were no differences in the cumulative percentage of lesions of LL between 2 groups (Figure 2, Online Figure S1). As shown in Table 3, there were no significant differences in either in-segment MLD (Restore DCB 1.64 ± 0.69 mm vs. SeQuent Please DCB 1.71 ± 0.58 mm; p = 0.37) or percentage stenosis (Restore DCB 38.9 ± 21.8% vs. SeQuent Please DCB 34.5 ± 21.1%; p = 0.12) between groups.
Clinical follow-up was completed in all patients at 12 months for the Restore DCB group and for 99.2% of patients in the SeQuent Please DCB group. Table 5 summarizes clinical events at 1 and 12 months in the ITT analysis. Compared with the SeQuent Please DCB group, TVR at 12 months was significantly higher in Restore DCB–treated patients (23.3% vs. 12.6; p = 0.03), whereas TLF at 12 months was similar in both groups: 13.3% (16 of 120) in Restore DCB–treated patients and 12.6% (15 of 119) in the SeQuent Please DCB group (p = 0.87). There was no cardiac death in either group, and the myocardial infarction rates were 2.5% (3 of 120) and 3.4% (4 of 119) in the Restore and SeQuent Please groups, respectively (p = 0.72). Thrombosis occurred in only 1 patient in the SeQuent Please arm. In Kaplan-Meier analysis (Figure 3), there were no differences in the cumulative incidence event rates (TLF, cardiac death, target vessel myocardial infarction, and target lesion revascularization) in the ITT population. The results were consistent in the ATS population (Online Table S4, Online Figure S2). Periprocedural myocardial infarction based on different definitions was shown in Online Table S5.
The present RESTORE ISR China trial demonstrated that the shellac-ammonium salt-based Restore DCB was noninferior to the iopromide-based SeQuent Please DCB, for the primary endpoint of 9-month in-segment LL in treating coronary ISR. Additionally, the rates of adverse clinical events were similar between both treatment groups within 1 year. Results of this new adequately powered head-to-head randomized trial comparing 2 different DCBs in ISR add important insights to the available clinical evidence on treatment strategy for ISR.
Much randomized data comparing DCBs with alternative percutaneous therapies for treatment of ISR are based on the iopromide-based SeQuent Please DCB. Thus, we designed this trial to provide evidence for regulatory approval in China by comparing the safety and efficacy of the Restore DCB with that of the SeQuent Please DCB. At 1-year follow-up, the study yielded comparable clinical and angiographic results between the SeQuent Please DCB and the Restore DCB with shellac-ammonium salt (a more hydrophobic excipient), which is expected to provide improved coating integrity and a suitable degree of coating lubricity.
Pre-dilation for neointimal modification might improve the performance of DCBs. In our study, lesion preparation was mandatory. Bail-out stent implantation after DCB was not needed, perhaps because a scoring or cutting balloon was used for pre-dilation in more than 50% of patients; in the ISAR-DESIRE 4 randomized trial, scoring balloon pre-dilation yielded better angiographic results (12). Full lesion preparation with appropriate technologies should be considered to improve the safety and efficacy of subsequent devices, including DCBs.
Several trials have confirmed the feasibility of using a DCB in DES ISR (11,13,14). In our clinical practice, almost all of the stents implanted are DES. As shown, patients enrolled in the RESTORE trial closely resemble those seen in daily clinical practice (DES vs. bare-metal stent ISR 98.4% vs. 1.6%). In this study, Restore DCB angioplasty showed a similar value when used to treat coronary ISR. We showed that the 9-month angiographic primary endpoint, LL, was similar between Restore DCB treatment and SeQuent Please DCB treatment. Because of accumulated experience with DCBs, 9-month LL appeared lower than that in the PEPCAD ISR China study (11). Other important angiographic endpoints in Restore DCB treatment, such as MLD and percentage stenosis of luminal diameter, also provided consistent evidence for the Restore DCB performance.
Importantly, using a DCB rather than a DES offers the advantage of delivering antiproliferative medication to the ISR lesion without additional deployment of metal. Furthermore, previous data showed a low relevance of in-segment percentage stenosis between post-procedural and follow-up outcomes when comparing the DES and DCB groups (14). In our study, the higher post-procedure percentage stenosis in the Restore DCB group could be secondary to higher reference vessel diameter, which did not result in more complications or binary restenosis at 9-month follow-up.
Despite the higher TVR, the safety endpoints, including death, myocardial infarction, and target lesion revascularization, remained at low levels in our Restore DCB group. There were few independent TVR predictors, including the number of diseased vessels, longer lesion, smaller reference vessel diameter, and planned routine angiographic follow-up (15). Given the similar baseline variables and target lesion revascularization, nontarget lesion-related disease progression and revascularization might underlie the higher rate of TVR in the Restore DCB group at 1-year follow-up; however, the underlying reasons need to be ascertained in larger trials with intravascular imaging.
We enrolled all 240 participants within 12 months and obtained 9-month angiographic results for 88.3% of the Restore DCB group and 85% of the SeQuent Please DCB group, and all the results for the 12-month clinical follow-up from 12 experienced clinical research centers. This constitutes an improvement from the DARE trial report, which needed more than 5 years to complete enrollment (14), thereby possibly strengthening the homogeneity and research quality of our clinical trial.
First, it was difficult for us to ensure enough power to be able to detect differences in clinical endpoints in this medium-sized trial of only 240 enrolled patients. However, angiographic surrogate endpoints such as late lumen loss have been widely used and validated in other trials evaluating the safety and efficacy of DCBs.
Second, we made no distinction of specific DES types for our analyses. In contrast, in daily clinical practice, we have found no evidence of different characteristics among DES with ISR.
Third, because recording of results from intravascular imaging techniques such as intravascular ultrasound and optical coherence tomography was not mandatory, we could not analyze the rate of intravascular imaging used in the study.
Fourth, considering that the new device would be used for the first time in a Chinese population, and the limited sample size and follow-up period, we avoided enrolling very high risk patients in this study. However, multivessel disease presence in 20% of patients and ISR distribution pattern have certain universality, which could provide a reference to clinical practice.
Limited sample size and short follow-up times could be the reasons for the low death rate seen in this study. Real-world evidence will be important to confirm the effectiveness of DCBs.
In the present multicenter, head-to-head, randomized trial, the new Restore DCB was noninferior to the reference standard SeQuent Please DCB for the primary endpoint of 9-month in-segment LL, and both devices had similar 1-year clinical outcomes. The study provided evidence for the efficacy and safety of the Restore DCB angioplasty in coronary ISR treatment.
WHAT IS KNOWN? DCB angioplasty offers an effective treatment for ISR. There is no adequately powered head-to-head randomized trial comparing different types of DCBS in patients with coronary ISR.
WHAT IS NEW? The present randomized trial demonstrated that Restore, a new paclitaxel-coated balloon, was noninferior to the reference standard SeQuent Please for angiographic in-segment LL, and both DCBs had similar clinical results at 1 year.
WHAT IS NEXT? Longer term follow-up and large-scale studies with primary clinical endpoints are needed to evaluate the clinical outcomes with the new Restore DCB in the treatment of DES ISR.
The authors thank the patients who participated in the RESTORE ISR China trial and appreciate the dedicated efforts of the clinical research collaborators in the RESTORE ISR China study organization and the contributions of the participating centers listed in the Online Appendix.
↵∗ Drs. Y. Chen and Gao contributed equally to this work.
This study was sponsored by Cardionovum through an institutional research grant. The executive committee, together with the sponsor, designed the RESTORE ISR China clinical trial. The sponsor had no role in data collection, data analysis, data interpretation, writing the manuscript, or the decision to submit the manuscript for publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- as-treated set
- Clinical Events Committee
- drug-coated balloon
- drug-eluting stent(s)
- in-stent restenosis
- late loss
- myocardial infarction
- minimal lumen diameter
- percutaneous coronary intervention
- target lesion failure
- target vessel revascularization
- Received August 14, 2018.
- Revision received September 9, 2018.
- Accepted September 10, 2018.
- 2018 American College of Cardiology Foundation
- Dibra A.,
- Kastrati A.,
- Alfonso F.,
- et al.
- Sabate M.,
- Raber L.,
- Heg D.,
- et al.
- ↵Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2018 Aug 25 [E-pub ahead of print].
- Gao L.,
- Qin Q.,
- Chen S.L.,
- et al.
- Pettersson J.S.,
- Fischer-Hübner S.,
- Bergmann M.
- Thygesen K.,
- Alpert J.S.,
- Jaffe A.S.,
- et al.
- Mehran R.,
- Rao S.V.,
- Bhatt D.L.,
- et al.
- Mehran R.,
- Dangas G.,
- Abizaid A.S.,
- et al.
- Alfonso F.,
- Cequier A.,
- Angel J.,
- et al.
- Xu B.,
- Gao R.,
- Wang J.,
- et al.
- Giannini F.,
- Latib A.,
- Ancona M.B.,
- et al.
- Baan J. Jr..,
- Claessen B.E.,
- Dijk K.B.,
- et al.