Author + information
- Received October 26, 2011
- Revision received January 9, 2012
- Accepted January 10, 2012
- Published online April 10, 2012.
- Harald Rittger, MD⁎,⁎ (, )
- Johannes Brachmann, MD†,
- Anil-M. Sinha, MD, DPhil‡,
- Matthias Waliszewski, MD§,
- Marc Ohlow, MD∥,
- Andreas Brugger, MD¶,
- Holger Thiele, MD#,
- Ralf Birkemeyer, MD⁎⁎,
- Volkhard Kurowski, MD††,
- Ole-A. Breithardt, MD⁎,
- Martin Schmidt, MD‡‡,
- Stefan Zimmermann, MD⁎,
- Sandra Lonke⁎,
- Moritz von Cranach⁎,
- The-Vinh Nguyen§§,
- Werner G. Daniel, MD⁎ and
- Jochen Wöhrle, MD§§
- ↵⁎Reprint requests and correspondence:
Dr. Harald Rittger, Universitätsklinikum Erlangen, Medizinische Klinik 2, Ulmenweg 18, 91054 Erlangen, Germany
Objectives This study sought to define the impact of paclitaxel-coated balloon angioplasty for treatment of drug-eluting stent restenosis compared with uncoated balloon angioplasty alone.
Background Drug-coated balloon angioplasty is associated with favorable results for treatment of bare-metal stent restenosis.
Methods In this prospective, single-blind, multicenter, randomized trial, the authors randomly assigned 110 patients with drug-eluting stent restenoses located in a native coronary artery to paclitaxel-coated balloon angioplasty or uncoated balloon angioplasty. Dual antiplatelet therapy was prescribed for 6 months. Angiographic follow-up was scheduled at 6 months. The primary endpoint was late lumen loss. The secondary clinical endpoint was a composite of cardiac death, myocardial infarction attributed to the target vessel, or target lesion revascularization.
Results There was no difference in patient baseline characteristics or procedural results. Angiographic follow-up rate was 91%. Treatment with paclitaxel-coated balloon was superior to balloon angioplasty alone with a late loss of 0.43 ± 0.61 mm versus 1.03 ± 0.77 mm (p < 0.001), respectively. Restenosis rate was significantly reduced from 58.1% to 17.2% (p < 0.001), and the composite clinical endpoint was significantly reduced from 50.0% to 16.7% (p < 0.001), respectively.
Conclusions Paclitaxel-coated balloon angioplasty is superior to balloon angioplasty alone for treatment of drug-eluting stent restenosis. (PEPCAD DES–Treatment of DES-In-Stent Restenosis With SeQuent® Please Paclitaxel Eluting PTCA Catheter [PEPCAD-DES]; NCT00998439)
Drug-eluting stents (DES) significantly reduce the occurrence of restenosis and the subsequent need for repeat revascularization (1,2). Nevertheless, the incidence of DES restenosis remains high due to the continuous increase in DES implantation (3). With present DES, complex lesions with a high restenotic potential are sufficiently treated (4), limiting the use of bare-metal stents (BMS) to patients not eligible for dual antiplatelet therapy (DAPT).
Paclitaxel-coated balloon (PCB) angioplasty is superior to plain old balloon angioplasty (POBA) (5) and noninferior to paclitaxel-eluting stent (PES) implantation for BMS restenosis (6). Whether the use of PCB angioplasty is also effective in DES restenosis has not been studied so far.
We evaluated in a randomized, multicenter, single-blinded trial the efficacy of a PCB angioplasty compared with POBA for DES restenosis in native coronary arteries.
From November 2009 to April 2011, 110 patients were recruited in 6 centers in the PEPCAD-DES (PEPCAD DES–Treatment of DES-In-Stent Restenosis With SeQuent® Please Paclitaxel Eluting PTCA Catheter) study. Inclusion criteria were an in-stent restenosis in sirolimus-eluting Cypher (Cordis, Warren, New Jersey) or Yukon (Translumina, Hechingen, Germany) stents, everolimus-eluting Xience (Abbott, Abbott Park, Illinois) or paclitaxel-eluting Taxus (Boston Scientific, Natick, Massachusetts) stents, reference vessel diameter of 2.5 to 3.5 mm, and lesion length of <22 mm. Exclusion criteria were thrombus within the target vessel, bifurcation lesion, multiple lesions in the target vessel, lesions in bypass grafts, total coronary artery occlusion, ostial or left main lesions, planned surgery within 6 months, and contraindication to DAPT. The protocol was approved by the ethics committee. All patients gave written informed consent (Clinical Trials ID: NCT00998439).
Study design and study procedures
Patients were randomly assigned to treatment of DES restenosis with PCB (SeQuent Please, B. Braun, Melsungen, Germany) or POBA alone. Pre-dilation with POBA according to the size of the restenotic stent was mandatory. The length of the PCB was chosen to overlap the lesion for at least 1 to 2 mm at the proximal and distal margin. Study balloons were inflated for 60 s at 10 bar. Patients received heparin to an activated clotting time of 200 to 250 s. The diameter of the study balloon had to be at least the diameter of the pre-dilation balloon and was left to the discretion of the operator. DAPT with acetylsalicylic acid 100 mg per day and clopidogrel 75 mg per day was prescribed for 6 months in both groups. Patients were followed by telephone or hospital visit at 30 days. Angiographic and clinical follow-up was scheduled at 6 months.
Quantitative coronary angiography
Angiographic measurements were done with the CAAS version 5.7 software (Pie Medical Imaging, Maastricht, the Netherlands) in the core lab of the University of Ulm, Ulm, Germany (4,7). The core lab was blinded to the randomized treatment strategy. Angiographic measurements were done separately at the target lesion treated by study balloon, within 5 mm proximal and distal to the target lesion, and over the total segment. Pattern of restenosis was classified according to Mehran et al. (8).
Statistical analysis and primary and secondary endpoints
To estimate the number of patients per group based on a 2:1 randomization, the 2-group Satterthwaite t test was used. Primary endpoint was late lumen loss at the target lesion at 6 months angiographic follow-up. With an assumed late lumen loss of 0.20 ± 0.30 mm in the drug-coated balloon (DCB) group and 0.80 ± 0.80 mm in the POBA group (6), the calculated number of patients were 64 in the PCB and 34 in the POBA groups to achieve 90% power. With an assumed dropout rate of 10%, the patient numbers to be recruited were 71 in the PCB and 38 in the POBA group. Categorical variables were compared using Pearson's chi-square test or Fisher exact test, when appropriate. All continuous variables are described with mean ± SD. Differences between proportions and t tests were computed with SPSS version 18.0 (IBM, Armonk, New York), whereas sample sizes were estimated with nQuery Advisor version 7.0 (Statistical Solutions, Saugus, Massachusetts).
Secondary angiographic endpoints were binary restenosis, minimal lumen diameter (MLD), and diameter stenosis at the target lesion and in the total segment. Secondary clinical endpoints were target lesion revascularization (TLR), myocardial infarction (MI), cardiac death, and stent thrombosis, defined according to the Academic Research Consortium criteria (9). Major adverse cardiac event was defined as a composite of cardiac death, MI attributed to the target vessel, and TLR.
A total of 110 patients with DES restenosis were randomized: 72 patients to treatment with PCB and 38 patients to POBA. Baseline clinical and angiographic characteristics were similar in the 2 groups (Table 1). There was a high frequency of patients with diabetes mellitus, with 36.1% in the PCB group and 34.2% in the POBA group (p = 0.84). Length (PCB: 19.8 ± 7.7 mm, POBA: 21.0 ± 7.7 mm; p = 0.41) and size (PCB: 2.75 ± 0.34 mm, POBA: 2.83 ± 0.39 mm; p = 0.29) of the restenosed DES were not different. First DES restenosis occurred in 46.4% of patients, and at least a second restenotic lesion in 53.6%.
Procedural success was 100% in both groups. All PCB catheters were successfully applied. Bailout stenting with a BMS was performed in 1 patient in each group due to unsatisfying balloon result or edge dissection.
Quantitative coronary angiography
Prior to percutaneous coronary intervention, lesion length, reference vessel diameter, diameter stenosis, and MLD did not differ between groups (Table 2). At baseline, the type of restenosis was focal in about two-thirds of patients in both treatment groups (Table 2). There was no difference in acute gain, with 1.49 ± 0.39 mm in patients treated with PCB, compared with 1.52 ± 0.49 mm in patients with POBA alone (p = 0.71). Post-percutaneous coronary intervention, MLD and diameter stenosis for target lesion and target segment were not different (Fig. 1). Angiographic follow-up rate was 86% and was obtained 6 ± 1 months after the index procedure. Ten clinically asymptomatic patients refused angiographic follow-up.
Late lumen loss at target lesion, the primary endpoint, was significantly lower in lesions treated with PCB compared with POBA alone, with 0.43 ± 0.61 mm versus 1.03 ± 0.77 mm (difference: −0.60 mm, 95% confidence interval: −0.889 to −0.312, p < 0.001). Late lumen losses for the total and the distal segments were also significantly lower in patients treated with PCB (Table 3). Furthermore, in lesions treated with PCB, MLD at follow-up was significantly larger (Fig. 1), and diameter stenosis and binary restenosis rate were significantly lower, both for target lesion and target segment (Table 3). Recurrent restenosis morphology according to Mehran et al. (8) for patients treated with PCB was focal (n = 8; 67%) or diffuse (n = 4; 33%). Pattern of restenosis in patients with POBA was focal (n = 13; 72%) or diffuse (n = 5, 28%).
Treatment with DCB significantly reduced late lumen loss in patients without diabetes mellitus (0.39 ± 0.54 mm vs. 0.91 ± 0.71 mm, p < 0.001), as well as in patients with diabetes mellitus (0.51 ± 0.72 mm vs. 1.45 ± 0.85 mm, p < 0.01), compared with POBA.
There were 4 patients with total occlusion in the POBA population versus none in the PCB group (p = 0.004). Late lumen loss for patients without occlusion was 0.43 ± 0.61 mm in the PCB group and 0.96 ± 0.77 mm in the POBA group (p = 0.001). Table 4 shows the angiographic outcome at 6 months according to type of restenotic stent.
Clinical follow-up was obtained in all patients. There was a significantly lower rate of TLR with use of the PCB with 15.3% (n = 11 of 72) compared with 36.8% (n = 14 of 38) with POBA alone (p = 0.01) (Table 4). Two of the 14 patients of the POBA group were forwarded to surgery. There was 1 MI in the POBA group attributable to the target vessel. Cardiac death (heart failure) occurred in 1 patient in the PCB and in 4 patients in the POBA group. There was another noncardiac death in the POBA group due to septicemia. The combined clinical endpoint defined by cardiac death, MI attributable to the target vessel, and TLR was significantly lower in patients treated with the PCB compared with patients treated with POBA alone (Table 5). There was no definite vessel thrombosis.
For DES restenosis, treatment with PCB was superior to POBA with respect to angiographic as well as clinical outcomes. The primary endpoint, late lumen loss at the target lesion, was significantly reduced. Furthermore, patients treated with PCB required significantly less repeat interventions.
For BMS restenosis, PCB was superior to POBA (5), with a sustained benefit for DCB-treated patients (10). In a small trial including patients with sirolimus-eluting stent (SES) restenosis, treatment with PCB was superior to POBA regarding late loss and restenosis rate (11). We now show in a randomized multicenter trial that use of PCB is superior to POBA in a larger population with restenosis in different types of DES. Furthermore, the pattern of restenosis was more complex in the POBA population, including total occlusions, which require a more complex reintervention compared with nonoccluded in-stent restenosis.
Late lumen loss was 0.43 ± 0.61 mm in our PCB population, clearly higher than the reported late lumen loss for PCB in BMS restenosis with 0.03 ± 0.48 mm (5) and for SES restenosis with 0.18 ± 0.45 mm (11). However, late lumen loss in our POBA population was also higher with 1.03 ± 0.77 mm compared with the reported late loss for POBA in BMS restenosis by Scheller et al. (5) with 0.74 ± 0.86 mm and for SES restenosis by Habara et al. (11) with 0.72 ± 0.55 mm, reflecting a more complex patient population with a higher restenotic risk in the PEPCAD-DES trial. Treatment with PCB significantly reduced the late loss in patients with diabetes mellitus, as well as in patients without diabetes mellitus, compared with POBA.
We did not compare PCB with DES in order to avoid an additional strut layer by another DES (12,13). Clinical long-term data with DES for DES restenosis are scarce. The observed late lumen loss in our DCB population is in the same range as reported for a DES treatment strategy for DES restenosis. In the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis 2) study, 450 patients with SES restenosis were randomized to treatment with SES or PES implantation (14). Late loss was 0.40 ± 0.65 mm versus 0.38 ± 0.59 mm for SES versus PES, compared with 0.43 ± 0.61 mm with PCB angioplasty in PEPCAD-DES. TLR rate was 17% for SES versus 15% for SES in the ISAR-DESIRE 2 study and did not differ numerically to our 15% TLR rate with PCB angioplasty. Of note, there was a small, but present, risk for stent thrombosis, with 0.4% in SES as well as in PES (14). With DES for DES restenosis, TLR rates have been reported in the range of 5.2% to 37% (15). Furthermore, occurrence of angiographic restenosis ranged from 16.7% to 42.9% (15) TLR rates were not different between repeat DES and POBA for DES restenosis in 213 patients at a mean follow-up period of 20 months (16) After adjustment for risk factors, there was a trend towards a higher rate of MI with DES versus POBA. Although use of DES for DES restenosis is a common treatment strategy, the use of a PCB should be considered as an effective treatment strategy for DES restenosis after successful balloon pre-dilation.
The number of patients was limited, since the study was powered for an angiographic endpoint. Different types of DES with restenosis were included in this study. Trial design was single blind and not double blind, with the use of an uncoated balloon in the POBA group, resulting in different lengths of the study balloon. We did not compare PCB with DES for treatment of DES restenosis. We did not use intravascular ultrasound to evaluate stent underexpansion or neointimal proliferation (15).
This randomized, multicenter PEPCAD-DES trial shows that treatment of DES restenosis with PCB angioplasty results in a significantly lower late lumen loss, binary restenosis rate, and major adverse cardiac event rate compared with uncoated balloon angioplasty. PCB angioplasty is superior to uncoated balloon angioplasty for treatment of DES restenosis.
The authors thank Heidi Langendorf, at the Klinikum Coburg, and Denny Herberger, at B. Braun Vascular Systems, for their support during the study.
Dr. Rittger has received speaker honoraria from B. Braun and Siemens. Dr. Waliszewski is a full-time employee of B. Braun. Dr. Wöhrle has relationships with B. Braun. All other authors have stated that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- dual antiplatelet therapy
- drug-coated balloon
- drug-eluting stent(s)
- myocardial infarction
- minimal lumen diameter
- paclitaxel-coated balloon catheter
- paclitaxel-eluting stent(s)
- plain old balloon angioplasty
- sirolimus-eluting stent(s)
- target lesion revascularization
- Received October 26, 2011.
- Revision received January 9, 2012.
- Accepted January 10, 2012.
- American College of Cardiology Foundation
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