Author + information
- Received April 2, 2012
- Revision received June 18, 2012
- Accepted July 10, 2012
- Published online October 30, 2012.
- Jochen Wöhrle, MD⁎,⁎ (, )
- Mariusz Zadura, MD†,
- Sven Möbius-Winkler, MD‡,
- Matthias Leschke, MD§,
- Christian Opitz, MD∥,¶,
- Waqas Ahmed, MD#,
- Paul Barragan, MD⁎⁎,
- Jean-Philippe Simon, MD††,
- Graham Cassel, MD‡‡ and
- Bruno Scheller, MD§§
- ↵⁎Reprint requests and correspondence:
Dr. Jochen Wöhrle, University of Ulm, Department of Internal Medicine II, Ulm 89081, Germany
Objectives This study sought to assess the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in an international, multicenter, prospective, large-scale registry study.
Background In small randomized trials, PCB angioplasty was superior to uncoated balloon angioplasty for treatment of bare-metal stent (BMS) and drug-eluting stent (DES) restenosis.
Methods Patients treated with SeQuent Please PCBs were included. The primary outcome measure was the clinically driven target lesion revascularization (TLR) rate at 9 months.
Results At 75 centers, 2,095 patients with 2,234 lesions were included. The TLR rate was 5.2% after 9.4 months. Definite vessel thrombosis occurred in 0.1%. PCB angioplasty was performed in 1,523 patients (72.7%) with DES or BMS restenosis and 572 patients (27.3%) with de novo lesions. The TLR rate was significantly lower in patients with PCB angioplasty for BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p < 0.001). The TLR rate did not differ for PCB angioplasty of paclitaxel-eluting stent and non–paclitaxel-eluting sten restenosis (8.3% vs. 10.8%, p = 0.46). In de novo lesions (small vessels), the TLR rate was low and did not differ between PCB angioplasty with and without additional BMS implantation (p = 0.31).
Conclusions PCB angioplasty in an all-comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES.
In randomized clinical trials, paclitaxel-coated balloon angioplasty (PCB) was superior to uncoated balloon angioplasty for the treatment of in-stent restenosis (ISR) in bare-metal stents (BMS) (1) as well as for the treatment of ISR in drug-eluting stents (DES) (2,3). For de novo coronary artery disease, the combination of a PCB plus an endothelial progenitor cell–capturing stent was superior regarding angiographic and clinical outcome compared with an endothelial progenitor cell–capturing stent alone (4). Furthermore, in small coronary arteries, PCB therapy without additional stent implantation has been associated with favorable results (5). The effect of PCB therapy for ISR was maintained in long-term follow-up (6). However, these studies were limited by moderate numbers of patients ranging from 50 to 131. Therefore, we performed the SeQuent Please World Wide Registry to demonstrate the efficacy and safety of treatment with the SeQuent Please PCB (B. Braun, Melsungen, Germany) in routine real-world practice.
The aim of this multicenter, international, all-comers registry study was to assess the safety and efficacy of PCB therapy in a large population with real-world treatment. Patients treated with the SeQuent Please PCB were included at 75 sites from 8 countries. Patients received 500 mg of aspirin before the intervention or were receiving long-term treatment. A clopidogrel loading dose of 600 mg was administered. Dual-antiplatelet therapy was recommended for at least 1 month. Patients with contraindications to dual-antiplatelet therapy, women with childbearing potential, and patients with contraindications or known hypersensitivity to acetylsalicylic acid, clopidogrel, paclitaxel, or heparin were not included. The protocol was ethically approved. All patients gave written informed consent. Data were captured using a common electronic case report form.
The PCB catheter was loaded with paclitaxel 3 μg/mm2. The length of the PCB catheter was chosen to exceed the target lesion for at least 2 to 3 mm. PCBs were inflated for 30 to 60 s with a minimum of 10 bar. BMS were implanted if the result after PCB therapy alone was not satisfactory because of recoil, residual stenosis, or dissections. In case of stent implantation outside the PCB-treated segment, another PCB was inflated to fully cover the stented segment with a PCB. Lesion length and vessel reference diameter were assessed using online quantitative coronary angiography or visual estimation.
Primary outcome measures
The primary endpoint was the clinically driven target lesion revascularization (TLR) rate at 9 months. The secondary endpoint was the rate of major adverse cardiac events (MACEs), defined as a composite of cardiac death, myocardial infarction, and TLR. Patients were followed by telephone or hospital visit at 9 months and will undergo 24-month follow-up. Furthermore, definite vessel thrombosis was defined in analogy to the Academic Research Consortium criteria for definite stent thrombosis (7).
Continuous variables are presented as mean (range) ± SD. Discrete variables are expressed as counts and percents. Categorical variables were compared using Pearson's chi-square test. Differences between proportions and t tests were computed using SPSS version 18.0 (SPSS, Inc., Chicago, Illinois). Time-to-event data are shown as Kaplan-Meier curves and were compared using log-rank tests. Multivariate regression analysis was performed to evaluate risk factors for the need for TLR after treatment of ISR and of de novo lesions. The following variables were included in both models: gender, diabetes mellitus, acute coronary syndromes, ostial lesion, and lesion location in a native vessel versus a graft vessel. Furthermore, BMS restenosis versus DES restenosis was included in ISR analysis and PCB versus PCB plus BMS in de novo lesion analysis.
Between February 2008 and November 2011, a total of 2,095 patients with 2,234 lesions were included. Seven hundred fifty-four patients had diabetes mellitus (36.0%), 1,561 had hyperlipidemia (74.5%), 1,795 had arterial hypertension (85.7%), 872 had histories of smoking (41.6%), 132 required dialysis (6.3%), and 1,552 were men (74.1%). PCB angioplasty was performed predominantly for the treatment of ISR (n = 1,523 [72.7%]). Treatment of de novo coronary artery disease was done in 572 patients (27.3%). For the total population, the target lesion was located in the left anterior descending coronary artery in 41.3%, the circumflex coronary artery in 24.6%, the right coronary artery in 29.1%, and grafts in 5.0%. The mean lesion length was 17.3 ± 8.0 mm, and the mean reference vessel diameter was 2.9 ± 0.5 mm.
For treatment of 2,234 lesions, a total of 2,347 PCBs were used (1.1 PCBs per lesion). The mean length of PCBs was 20.3 ± 5.5 mm, with a mean diameter of 2.9 ± 0.4 mm. The mean inflation pressure was 12.9 ± 3.8 bar. After PCB angioplasty, dissections were documented in 4.7% (n = 104), requiring additional stent implantation in 82 of these cases.
Clinical follow-up was obtained after 9.4 ± 2.3 months. The primary outcome measure, TLR, was observed in 5.2% of the total population. MACEs occurred in 6.7% and were a composite of cardiac death in 1.8% and myocardial infarction in 0.8% plus TLR. The target vessel revascularization (TVR) rate was 6.2%. Thrombotic events at the target lesion occurred in 0.1% of the total population (n = 2).
ISR: BMS versus DES
In 1,207 patients with 1,264 ISR lesions, the type of restenosed stent was documented. PCB angioplasty was performed in 743 patients with 782 BMS restenoses and in 464 patients with 482 DES restenoses. The frequency of cardiovascular risk factors was similar between groups except for a significantly higher rate of arterial hypertension in patients with BMS restenosis (Table 1). Baseline lesion characteristics and procedural data did not differ except for a higher rate of graft and ostial lesions and a lower rate of American Heart Association/American College of Cardiology type B/C lesions in DES restenosis compared with BMS restenosis (Table 2). The length of the PCB treated segment was 3 to 4 mm longer compared with the lesion lengths for both DES and BMS restenosis. Technical success was high, ranging between 98.3% and 99.3%.
The primary outcome measure, TLR, was significantly lower in BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p < 0.001) (Fig. 1). Acute coronary syndromes (p = 0.034), ostial lesions (p = 0.023), graft lesions (p = 0.004), and DES restenosis (p < 0.001) were significant risk factors for TLR. Furthermore, the frequency of MACEs was significantly lower for BMS restenosis compared with DES restenosis (Figs. 1 and 2).⇓ There were 2 definite vessel thromboses, 1 in each group, resulting in vessel thrombosis rates of 0.2% for DES restenosis and 0.1% for BMS restenosis (p = 0.75). The vessel thrombosis in DES ISR occurred 169 days after PCB treatment in a segment with previous brachytherapy. The vessel thrombosis in BMS ISR occurred 53 days after PCB angioplasty, after stopping dual-antiplatelet therapy for a surgical procedure.
In 389 patients, the type of restenosed DES was documented. There were 129 patients with paclitaxel-eluting stent (PES) restenosis and 260 patients with non-PES restenosis. Baseline and procedural data did not differ between both groups except for higher frequencies of arterial hypertension in PES restenosis (90.9% vs. 81.6%, p = 0.02) and total occlusions (10.1% vs. 4.2%, p = 0.024) compared with non-PES restenosis. There were no differences for PCB treatment of PES restenosis compared with non-PES restenosis with respect to MACEs, TLR, TVR, myocardial infarction, or cardiac death (Fig. 3).
De novo lesions
There were 491 patients with de novo lesions and treatment with PCBs alone (n = 390) or PCBs plus BMS (n = 101). Baseline and procedural data for patients with PCBs versus PCBs plus BMS were almost similar (Tables 3 and 4).⇓⇓ Lesions were located in small vessels, demonstrated by a mean reference diameter of 2.6 ± 0.5 mm. Rates of MACEs, TLR, and TVR were low and did not differ in patients with versus without additional stent implantation (Fig. 4). Female sex (p = 0.043) and the presence of diabetes mellitus (p = 0.023) were significant predictors for TLR.
The main finding of the prospective, multicenter, all-comers SeQuent Please World Wide Registry was that treatment with PCBs in a real-world setting including a large population with more than 2,000 patients was safe and resulted in a low rate of clinically driven TLR. PCB angioplasty in BMS restenosis resulted in a significantly lower TLR rate compared with PCB angioplasty for DES restenosis, with no difference regarding the type of DES. For de novo lesions in small vessels, the TLR rate was low both for treatment with PCB alone and with BMS.
In the SeQuent Please World Wide Registry, PCB angioplasty was predominantly used for the treatment of restenosis in BMS or DES. Over 9 months of clinical follow-up, the TLR and MACE rates were low, at 5.2% and 6.7%, respectively. Furthermore, the frequency of vessel thrombosis was only 0.1% in ISR.
Randomized trials have shown that PCB angioplasty is superior to uncoated balloon angioplasty for the treatment of BMS restenosis and DES restenosis (1–3). In these trials with angiographic follow-up, the need for TLR after PCB angioplasty was 0% for 26 patients with BMS restenosis within 12-month follow-up (1) and 4% in 54 patients with BMS restenosis within 12 months (7), compared with 4.3% in 25 patients with sirolimus-eluting stent (SES) restenosis within 6 months (2) and 15.3% in 72 patients with DES restenosis (3). In the SeQuent Please World Wide Registry, the TLR rate was significantly higher in patients with DES restenosis compared with BMS restenosis. DES restenosis was an independent risk factor for TLR. This may be explained by higher late loss after treatment of DES restenosis compared with BMS restenosis. This is probably triggered by the use of DES for lesions with a high risk for restenosis, while lesions with a low risk for restenosis are treated with BMS. In randomized trials with angiographic follow-up, mean late luminal loss with PCB angioplasty was 0.03 ± 0.48 mm for BMS restenosis (1), 0.18 ± 0.45 mm for SES restenosis (2), and 0.43 ± 0.61 mm for DES restenosis (3). Another possible explanation might be that in DES restenosis, there was already a failure of local antiproliferative drug therapy, whereas BMS restenosis is still naive regarding antiproliferative drug treatment. This is supported by our data showing no difference in TLR with PCB for PES and non-PES restenosis. Furthermore, this effect seems to be similar with DES. In the Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis I trial (8), patients with BMS restenosis were randomized to uncoated balloon angioplasty and PES or SES implantation. The TVR rate differed significantly, at 33%, 19%, and 8%, respectively, and was higher than our 5.2% TVR rate in the SeQuent Please World Wide Registry using PCB angioplasty. In the Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis II trial (9), patients with SES restenosis were randomized to treatment with PES or SES. Late luminal loss for treatment with DES was clearly higher in DES restenosis (0.38 mm for PES, 0.40 mm for SES) (9) compared with BMS restenosis (0.26 mm for PES, 0.10 mm for SES) (8).
In a small registry, PCB angioplasty for de novo lesions in small coronary arteries was associated with a TLR rate of 12% within 12 months (5). We now demonstrate in more than 400 patients with de novo lesions that PCB angioplasty with or without BMS was safe and associated with low TLR rates (1.0% and 2.4% at 9 months). Diabetes mellitus was a significant predictor for TLR.
This was a prospective, large-scale registry adding important new insight into PCB therapy to the moderately sized randomized trials. Therefore, comparison of subgroups is only hypothesis generating and needs to be further evaluated. There was no angiographic core lab. Therefore, the frequency and impact of geographic miss cannot be reported.
PCB angioplasty in an all-comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES.
The SeQuent Please World Wide Registry was supported by B. Braun (Berlin, Germany). Dr. Wöhrle has received grants and speaker's honoraria from B. Braun. Dr. Zadura has received speaker's honoraria from B. Braun. Dr. Möbius-Winkler is a consultant for Boston Scientific. Dr. Leschke has received grants from B. Braun. Dr. Scheller has received speaker's honoraria from B. Braun; and is named as a coinventor on a patent application for various methods of restenosis inhibition, including the technique used in this trial, by Charité University Hospital (Berlin, Germany). 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)
- drug-eluting stent(s)
- in-stent restenosis
- major adverse cardiac event(s)
- paclitaxel-coated balloon
- paclitaxel-eluting stent(s)
- sirolimus-eluting stent(s)
- target lesion revascularization
- target vessel revascularization
- Received April 2, 2012.
- Revision received June 18, 2012.
- Accepted July 10, 2012.
- American College of Cardiology Foundation
- Habara S.,
- Mitsudo K.,
- Kadota K.,
- et al.
- Rittger H.,
- Brachmann J.,
- Sinha A.M.,
- et al.
- Wöhrle J.,
- Birkemeyer R.,
- Markovic S.,
- et al.
- Scheller B.,
- Clever Y.P.,
- Kelsch B.,
- et al.
- Cutlip D.E.,
- Windecker S.,
- Mehran R.,
- et al.
- Mehilli J.,
- Byrne R.A.,
- Tiroch K.,
- et al.