Author + information
- Received July 19, 2013
- Revision received August 8, 2013
- Accepted August 14, 2013
- Published online February 1, 2014.
- Bo Xu, MBBS∗,
- Runlin Gao, MD∗∗ (, )
- Jian'an Wang, MD†,
- Yuejin Yang, MD∗,
- Shaoliang Chen, MD‡,
- Bin Liu, MD§,
- Fang Chen, MD‖,
- Zhanquan Li, MD¶,
- Yaling Han, MD#,
- Guosheng Fu, MD∗∗,
- Yelin Zhao, MMSc∗,
- Junbo Ge, MD††,
- PEPCAD China ISR Trial Investigators
- ∗Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, Beijing, China
- †Department of Cardiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- ‡Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- §Department of Cardiology, Jilin University the Second Hospital, Changchun, China
- ‖Department of Cardiology, Affiliated Anzhen Hospital of Capital Medical University, Beijing, China
- ¶Department of Cardiology, Liaoning Provincial People's Hospital, Shenyang, China
- #Department of Cardiology, Shenyang Northern Hospital, Shenyang, China
- ∗∗Department of Cardiology, Affiliated SRRS Hospital of Zhejiang University School of Medicine, Hangzhou, China
- ††Department of Cardiology, Affiliated Zhongshan Hospital of Fudan University, Shanghai, China
- ↵∗Reprint requests and correspondence:
Dr. Runlin Gao, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, 167 Bei Li Shi Road, Xicheng District, Beijing 100037, China.
Objectives The intention of the PEPCAD China ISR (A Prospective, Multicenter, Randomized Trial of Paclitaxel-Coated versus Paclitaxel-Eluting Stent for the Treatment of Drug-Eluting Stent In-Stent Restenosis) was to demonstrate the efficacy of paclitaxel-coated balloon (PCB) angioplasty in a non-European patient population with coronary drug-eluting stent in-stent restenosis (DES-ISR).
Background The treatment of DES-ISR is still challenging with no established best strategy. Moreover, there is no study on the effect of PCB in the treatment of ISR in the Chinese population.
Methods PEPCAD China ISR was a 220-patient randomized (1:1), single-blind prospective multicenter trial conducted in China. Patients with coronary DES-ISR received either PCB (SeQuent Please, B. Braun Melsungen AG, Melsungen, Germany) or paclitaxel-eluting stent (Taxus Liberté, Boston Scientific, Natick, Massachusetts) treatment. The primary endpoint was in-segment late lumen loss at 9 months.
Results There were no significant baseline differences between both treatment groups in terms of patient, lesion, or procedural characteristics. At 9 months, in-segment late lumen loss in the PCB group was noninferior to that of the paclitaxel-eluting stent group (0.46 ± 0.51 mm vs. 0.55 ± 0.61 mm; difference: −0.06 mm with 95% confidence interval: −0.23 to 0.10; p for noninferiority = 0.0005). The 9-month rate of binary restenosis and 12-month composite clinical event rates were not significantly different between groups.
Conclusions In a randomized trial of 220 patients, angioplasty with a PCB was noninferior to paclitaxel-eluting stent implantation when used to treat DES-ISR. On the basis of these, as well as previous randomized trial data, PCB angioplasty offers an effective treatment for DES-ISR without the necessity of implanting additional metal layers for drug release. (A Safety and Efficacy Study of Paclitaxel-Eluting Balloon to Paclitaxel-Eluting Stent [PEPCAD]; NCT01622075)
Previous studies have shown that paclitaxel-coated balloon (PCB) angioplasty (Paccocath, Bavaria Medizin Technology, Oberpfaffenhofen, Germany) is safe and effective in treating coronary bare-metal stent in-stent restenosis (BMS-ISR) (1–5), which led to a class IIa, level B recommendation by the European Society of Cardiology for BMS-ISR (6) with long-term clinical benefits up to 5 years (7).
There are emerging data regarding the use of PCB angioplasty for the treatment of coronary drug-eluting stent (DES) ISR as well. These data currently comprise a small-scale Japanese study by Habara et al. (8), the PEPCAD-DES (Treatment of DES In-Stent Restenosis With SeQuent Please Paclitaxel-Eluting PTCA Catheter) trial (9), and the ISAR DESIRE 3 (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches) trial (10). In these trials (8–10), PCB, compared with conventional balloon angioplasty, revealed significantly lower late lumen loss (LLL) and major adverse cardiac events. In addition, in the ISAR DESIRE 3 trial (10), PCB angioplasty was demonstrated to be noninferior to paclitaxel-eluting stent (PES) implantation for DES-ISR.
Despite the obvious benefit of not adding additional metal layers to an ISR lesion, DES were studied for the use in DES-ISR relative to their eluted drugs. Cosgrave et al. (11) found that repeat DES implantation in DES-ISR did not differ when the eluted drug was changed compared with the use of the same DES in the original DES-ISR (e.g., PES for PES). In contrast, Alfonso et al. (12) could not confirm these results and suggested the implantation of a different type DES for DES-ISR (e.g., PES after sirolimus-eluting stents). Due to these conflicting results and the attractive stent-free treatment of the DES-ISR option, PCB angioplasty was chosen to be the treatment group compared with PES for obvious methodological reasons. A highly undervalued aspect of clinical trials is the increasing regulatory complexity of emerging markets and potential bias due to ethnically selected patient populations (13). Therefore, this trial was also designed to adequately confirm the validity of previous study results in a Chinese patient population. Besides the confirmation of the clinical and angiographic results from a large European trial (10), the PEPCAD China ISR (A Prospective, Multicenter, Randomized Trial of Paclitaxel-Coated Balloon versus Paclitaxel-Eluting Stent for the Treatment of Drug-Eluting Stent In-Stent Restenosis) was also designed to meet Chinese regulatory requirements for the approval of the used PCB study device.
PEPCAD China ISR is a randomized (1:1), single-blind, prospective, multicenter trial conducted at 17 Chinese study sites. Patients received either PCB (SeQuent Please, B. Braun Melsungen AG, Melsungen, Germany) or PES (Taxus Liberté, Boston Scientific, Natick, Massachusetts) treatment. Major inclusion criteria were as follows: age 18 to 80 years; DES restenosis patterns Mehran types I to III (14); reference diameters 2.5 to 4.0 mm; length ≤30 mm; and percentage of diameter stenosis ≥70% or ≥50% with documented myocardial ischemia. Major exclusion criteria included the following: acute myocardial infarction within 1 week; bifurcation with side branch diameter ≥2.5 mm; evidence of extensive thrombus in the target vessel; severe chronic heart failure or New York Heart Association class IV; severe valvular heart disease; stroke within 6 months prior to the procedure; and/or severe renal failure (glomerular filtration rate <30 ml/min). The baseline medical therapies including, for example, nitrates, beta-blockers, and statins were routinely used according to guidelines. Aspirin 300 mg was given orally within 24 h before the procedure. Clopidogrel was given at a dose of 300 mg 6 h before the procedure or 75 mg/day 3 days before the procedure. After the procedure, dual antiplatelet therapy (aspirin 100 mg/day indefinitely and clopidogrel 75 mg/day for at least 12 months) was recommended.
The primary endpoint was in-segment LLL at 9 months. Secondary endpoints included: rates of acute success (device, lesion, and procedural success); 9-month percentage of diameter stenosis; 9-month binary restenosis rate; and in-device LLL at 9 months. Furthermore, secondary endpoints were the rates of target lesion failure (TLF) at 1, 6, 9, and 12 months. TLF was defined as the composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization. In addition, definite/probable stent thrombosis rates defined by the Academic Research Consortium were documented. The protocol was approved by all ethics committees responsible for all participating centers (see Online Appendix). An independent clinical event committee consisting of 3 non-study-site participants evaluated potential device- or procedure-related adverse and serious adverse events. All patients gave written informed consent prior to randomization.
Quantitative coronary angiography
Angiographic measurements were conducted offline with the QAngio XA software (version 7.2, Medis, Leiden, the Netherlands) at an experienced core lab (CCRF, Beijing Co. Ltd., Beijing, China). The core lab was blinded relative to the treatment groups. Angiographic measurements were done separately at the target lesion over the entire length of the study device, within 5 mm proximal and distal of the target lesion, and over the entire segment. Restenosis patterns were classified according to their focal or diffuse patterns as commonly applied in patients with DES-ISR (8,9).
Statistical planning and analyses
All statistical analyses were done at the Division of Biometrics, National Center for Cardiovascular Diseases of China (Beijing, China).
The primary objective was to demonstrate the noninferiority of the in-segment LLL after PCB angioplasty compared with the corresponding LLL following PES implantation. The estimated in-segment LLL of PES was 0.45 ± 0.50 mm, the noninferiority margin of LLL was pre-specified as 0.22 mm. Under the 1-sided significance level alpha of 0.025 and an estimated 25% loss to angiographic follow-up, 220 patients will yield 80% power to detect noninferiority of PCB treatment versus PES implantation. For angiographic endpoints, a lesion-based analysis was planned.
Continuous variables were expressed as mean ± SD and compared by the Student t test. Categorical variables were expressed as frequencies and percentages and were compared by the chi-square test or Fisher exact test. The analysis of covariance was used as the primary analysis for LLL. The pre-specified covariates in this model were post-procedural MLD and study site. After eliminating the nonsignificant interaction between treatment and study site, the difference of the LLL between the 2 groups as well as the 95% confidence intervals (CIs) would be estimated by the least-square estimation. Cumulative incidence of TLF at 12 months was estimated by the Kaplan-Meier method and compared with the log-rank test. All significant levels were 0.05, and all analyses were performed with SAS (version 9.13, SAS Institute, Cary, North Carolina).
Between March 25, 2011 and April 16, 2012, 220 patients were randomized to either PCB treatment or PES implantation. Five patients withdrew their informed consent forms, leaving 109 patients for PCB treatment and 106 for PES implantation (Fig. 1). Baseline cardiovascular risk factors did not differ significantly between the 2 randomized study groups (Table 1).
In the PCB group, 113 lesions (Table 2) were treated, whereas in the PES control group, 108 stents were implanted. There were no significant differences of target vessel distributions and Mehran classifications. Neither reference vessel diameters (2.66 ± 0.38 mm, 2.72 ± 0.44 mm, p = 0.33) nor lesion lengths (12.52 ± 6.55 mm, 13.08 ± 7.13 mm, p = 0.54) were significantly different between groups. Likewise, minimal lumen diameters (MLD) and percentages of diameter stenosis behaved similarly.
Relative to the procedural and device characteristics (Table 3), study device balloon pressures were lower when the PCB was used (PCB: 12.4 ± 3.3 atm vs. PES: 13.5 ± 2.7 atm, p = 0.008). Moreover, balloon inflation times were significantly longer in the PCB group (PCB: 44.5 ± 13.1 s vs. PES: 14.0 ± 10.8 s, p < 0.0001). The most important lesion morphological differences were the post-procedural in-device MLD, which was significantly lower in the group PCB (2.39 ± 0.37 mm vs. 2.56 ± 0.44 mm, p = 0.003) than in the PES group. The percentage of diameter stenosis was higher after PCB treatment than after PES implantation (10.5 ± 7.2% vs. 7.1 ± 6.3%, p < 0.001). The acute in-device lumen gain, however, was lower after PCB treatment than with PES implantation (1.54 ± 0.43 mm vs. 1.70 ± 0.47 mm, p = 0.009). Among the 113 lesions in the PCB group, BMS bailout stenting procedures because of edge dissections were performed in 5 lesions (4.4%). Device and lesion crossing success rates did not differ between groups. In both groups, most ISR treated were the result of limus-releasing stents (e.g., Cypher, Cordis Corp., Miami Lakes, Florida; Firebird, Microport Co. Ltd., Shanghai, China; Excel, JW Medical Systems, Weihai, China), whereas the remainder were PES-ISR (PCB: 97.3% vs. PES: 98.1%). Definite or probable stent thrombosis rates were not different between the 2 groups during the first 12 months following percutaneous coronary intervention.
Angiographic follow-up results (Table 4) were obtained in 80% of the total study population. MLD before, after, and at the 9-month follow-up (Fig. 2) were similar. The primary endpoint in-segment LLL did not differ between PCB and PES treatment (0.46 ± 0.51 mm vs. 0.55 ± 0.61 mm, difference: −0.06 mm; 95% CI: –0.23 to 0.10; p for noninferiority = 0.0005). Except for the proximal edge MLD and the proximal edge LLL, there were no differences in any quantitative coronary angiography parameters (Online Table 1). MLD at the proximal ISR edge in the PCB group was larger (2.63 ± 0.43 mm vs. 2.45 ± 0.61 mm, p = 0.03) and the proximal edge LLL was lower (0.10 ± 0.30 mm vs. 0.27 ± 0.41 mm, p = 0.002) as compared with the corresponding results after PES implantation.
Patterns of restenosis according to Mehran classification did not differ between study groups. Nevertheless, the focal versus diffuse pattern analysis revealed that there were numerically more focal ISR patterns associated with PCB angioplasty than with PES implantation (72.2% vs. 50.0%); however, these were not statistically significant (p = 0.16).
Clinical results at 12 months
Clinical results at 1 and 12 months (Table 5) did not differ between the 2 groups in the intention-to-treat or as-treated-set analyses. The main driver for TLF at 12 months was target lesion revascularization. The 12-month TLF rates in the as-treated-set analysis were 15.5% (17 of 110) in PCB patients and 17.5% (18 of 103) in the PES group (p = 0.69). In the absence of cardiac death, the myocardial infarction rates were 2.7% (3 of 110) and 6.8% (7 of 103) in the PCB and PES groups, respectively (p = 0.20).
Referring to the Kaplan-Meier analyses (Fig. 3), there were no differences in the cumulative composite incidence rates consisting of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization in the intention-to-treat analysis (p = 0.87) and in the as-treated-set analysis (p = 0.51).
The results of this moderate-sized randomized trial of PCB angioplasty versus PES for DES-IRS demonstrated that PCB angioplasty was noninferior in terms of in-segment LLL to PES implantation in patients with DES-ISR. Additionally, the rates of adverse clinical events were similar between both treatment groups with 12-month clinical follow-up. Overall, these results, obtained entirely within a Chinese patient population, are in agreement with previous studies that have compared PCB angioplasty with conventional balloon angioplasty (7–10) and to repeat DES implantation (10).
Although ISR occurs with a lower frequency among patients treated with DES than with BMS, when ISR occurs, it can lead not only to a recurrence of stable angina symptoms but in some cases has also been associated with unstable angina and/or myocardial infarction (15,16). The majority of patients with ISR additionally have to undergo repeat revascularization procedures by either percutaneous coronary intervention or coronary artery bypass graft, and even after repeat percutaneous coronary intervention, the rate of recurrence of ISR is higher than among patients with de novo DES implantation (11). As a result, there remains active interest in therapies that are both effective and safe at treating DES-ISR.
Whereas repeat DES implantation is a viable strategy for the treatment of DES-ISR, it is intuitively appealing to avoid placement of another metal layer within an existing stent with ISR. The original PCB technology that was used in this trial (SeQuent Please, Paccocath) has a drug concentration of 3 μg/mm2 paclitaxel embedded in an iopromide spacer matrix (17).
In this study, we demonstrated noninferiority of PCB angioplasty to PES for the treatment of DES-ISR. Although noninferiority of late loss was demonstrated, we did measure 0.46 mm for in-segment late loss, which is somewhat higher than the analogous LLL of 0.32 mm by Rittger et al. (9) and 0.37 mm by Byrne et al. (10). Nonetheless, PCB angioplasty was very comparable with PES implantation and, compared with the results obtained from BMS-ISR populations, the amount of in-segment LLL can be expected to be twice as high in patients with DES-ISR. Unfortunately, the assessment of previous multilayer stenting could not be routinely determined in our study population during the index procedure.
Despite the lower acute in-device luminal gain (Table 3) in the PCB group (1.54 ± 0.43 mm vs. 1.70 ± 0.47 mm, p = 0.009), the in-device MLD at 9-month follow-up are not significantly different (1.85 ± 0.60 mm vs. 1.89 ± 0.75 mm, p = 0.66), which means that intimal hyperplasia can be expected to be more pronounced with PES implantation. The other potential ramification of this finding is that acute angiographic results may appear to be discouraging but may lead to sustained angiographic benefits at a 9-month follow-up. This finding is also supported by the recent publication by Agostoni et al. (18) that described morphological and functional outcomes after drug-coated balloon angioplasty for ISR. Interestingly, our MLD curve at follow-up for the PES patients shows an increased slope for the bottom 30% of MLD that appears similar to the findings by Unverdorben et al. (3), who used the Taxus stent as a comparator in their PEPCAD II (Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease II) trial. It seems that a significant subgroup of patients (20% to 30%) do not seem to benefit from stent-mediated paclitaxel release to treat ISR.
Noticeably, the proximal edge MLD in the PCB group is larger than that in the PES group, whereas the reference vessel diameters are similar at 9-month follow-up. This may be because of the fact that in the PES control group, the balloon is slightly longer than the actual stent (balloon overhang), extending over the proximal and distal stent edges. This, however, may lead to vessel damage proximal and distal to the stent edge where the drug is not being released (no stent struts for drug release in balloon-dilated vessel segments). This, in turn, may lead to further LLL. In contrast, when using the PCB, all vessel injury in the balloon-dilated lesion and neighboring segments caused by either the pre-dilation or the low-pressure PCB dilation is covered with the drug. This suggests that drug-coated balloon angioplasty may have less of an edge effect than has commonly been observed with DES.
Our findings confirm the results by Byrne et al. (10), who demonstrated clinically similar results with PCB angioplasty versus PES implantation. Nevertheless, the clinical benefit of a stent-free drug release when using PCB and thereby avoiding additional metal layers seems highly attractive for a variety of reasons (vaso-motility, less mechanical irritation, potential to reduce dual antiplatelet therapy).
The balance of smaller noninferiority margin versus increasing sample size is always an issue. We sensed, however, that a clinically acceptable margin was pre-defined despite the fact that the noninferiority margin was one-half of the expected effect size. Although this study was powered for an angiographic endpoint, the number of patients was not sufficient to detect differences in clinical endpoints. Despite the fact that patients with DES-ISR were recruited, the exact type of failed DES could not be determined in all patients. Moreover, additional imaging techniques such as optical coherence tomography to obtain more detailed lesion morphologic data were not feasible for all patients in this trial.
This multicenter, randomized trial demonstrates the safety and efficacy of PCB angioplasty and noninferiority versus PES treatment in a non-European study population in need of ISR treatment after limus-eluting stent failure.
The authors thank the regulatory support by Dr. Shi Pan at the Medical Scientific Affairs Department of B. Braun in China and the linguistic advice of Dr. Matthias Waliszewski at B. Braun's Medical Scientific Affairs unit in Berlin, Germany. The authors appreciate the dedicated effort of the clinical research collaborators in the PEPCAD China ISR study organization and the contributions of the participating centers listed in the appendix.
For the list of participating study centers and supplemental table please see the online version of this paper.
This trial was sponsored by B. Braun Medical International Trading Co., Ltd. Drs. Xu, Gao, Wang, Liu, and Chen, and Dr. Li have received research grants from B. Braun. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- confidence interval(s)
- drug-eluting stent(s)
- in-stent restenosis
- late lumen loss
- minimal lumen diameter(s)
- paclitaxel-coated balloon(s)
- paclitaxel-eluting stent(s)
- target lesion failure
- Received July 19, 2013.
- Revision received August 8, 2013.
- Accepted August 14, 2013.
- American College of Cardiology Foundation
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