Elutax paclitaxel-eluting balloon followed by bare-metal stent compared with Xience V drug-eluting stent in the treatment of de novo coronary stenosis: A randomized trial Francesco Liistro, MD, a Italo Porto, MD, PhD, a Paolo Angioli, MD, a Simone Grotti, MD, a,b Kenneth Ducci, MD, a Giovanni Falsini, MD, a and Leonardo Bolognese, MD a Arezzo, and Siena, Italy
Background Paclitaxel-eluting balloons (PEBs) are a promising alternative to drug-eluting stent (DES) in the treatment of coronary stenoses. The aim of our study was to compare the 9-month restenosis rates of a strategy of predilatation with PEB followed by bare-metal CoCr stent (PEB + BMS group) versus implantation of everolimus DES (DES group). Methods This randomized, single-center study planned to enroll 366 patients with stable angina (183 patients per arm) undergoing percutaneous coronary intervention of a de novo, native coronary artery stenosis ≤ 15 mm in length. Primary end point, in a noninferiority study design, was 9-month binary angiographic restenosis. A frequency-domain optical coherence tomography substudy investigated the percentage of uncovered stent struts per lesion, the percentage of malapposed/ uncovered struts per lesion, and the percentage of net volume obstruction at 9-month follow-up among the first consecutive 30 patients enrolled in the PEB + BMS group. Results
The study was prematurely halted after enrollment of 125 patients, 59 in the PEB + BMS group and 66 in the DES group, because of excess of ischemia-driven target lesion revascularization in the PEB + BMS group. When all the enrolled patients completed their follow-up, IDLTR rates were 14% in the PEB + BMS versus 2% in DES group (P = .001). Binary restenosis, either in-stent or in-segment, was significantly higher in the PEB + BMS compared with DES group (17% vs 3% [P = .01] and 25% vs 4% [P = .009] respectively). Frequency-domain optical coherence tomography demonstrated important neointimal regrowth in the PEB + BMS group, similar to historical BMS data.
Conclusion In the treatment of de novo coronary stenosis, a strategy of predilatation with PEB before BMS implantation was significantly inferior to implantation of an everolimus DES stent in terms of 9-month target lesion revascularization. Frequency-domain optical coherence tomography data confirm the lack of efficacy of this strategy. (Am Heart J 2013;166:920-6.)
In the last 10 years, drug-eluting stents (DESs) have progressively replaced bare-metal stents (BMSs) in coronary revascularization procedures. 1 Dependency on long-term dual-antiplatelet therapy, however, has become a major issue for patients receiving these
From the aCardiovascular and Neurologic Department, San Donato Hospital, Arezzo, Italy, and bDepartment of Cardiovascular Diseases, University of Siena, Le Scotte Hospital, Siena, Italy. Presented, in part, at the Transcatheter Cardiovascular Therapeutics, November 2011, San Francisco, CA, and published in an abstract form (J Am Coll Cardiol. 2011;58(Suppl B):B5). Submitted March 8, 2013; accepted August 7, 2013. Reprint requests: Italo Porto, MD, PhD, Cardiovascular and Neurologic Department, San Donato Hospital, Via Pietro Nenni 22, 52100 Arezzo, Italy. E-mail: [email protected] 0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2013.08.023
devices. 2 Recently, paclitaxel-eluting balloons (PEBs) have emerged as a potential alternative to DES. Paclitaxel was identified as the primary drug for balloon coating because of its rapid release and prolonged retention. 3 Paclitaxel-eluting balloon technology demonstrated safety and efficacy in preclinical 4 and in randomized trials for patients with coronary in-stent restenosis, 5 de novo lesions in small vessels, 6 lesions in the superficial femoral artery, 7 and, recently, also for carotid in-stent restenosis. 8 Potential advantages of PEB over DES include the following: (1) homogenous drug transfer to the entire vessel wall; (2) rapid, sustained release of high concentrations of the drug in the vessel wall; and (3) absence of polymer. 3 Elastic recoil and flow-limiting dissections, 9,10 however, the Achilles' heel of balloon angioplasty (BA), are also potential limitations of PEB, and in the absence of the mechanical scaffolding provided by stent struts, PEB angioplasty of complex coronary lesions is not
American Heart Journal Volume 166, Number 5
recommended. We elected to compare, in terms of a 9month restenosis, an interventional strategy based on lesion predilatation with PEB followed by cobalt-chromium BMS implantation with a strategy of DES implantation in patients undergoing coronary intervention for a de novo coronary stenosis.
Materials and methods Patient population and study design The study was designed as a prospective, randomized, singlecenter, investigator-initiated, single-blind study. The aim, in patients undergoing percutaneous coronary intervention (PCI), was to compare the 9-month restenosis rate of a strategy of predilatation with Elutax PEB (Aachen Resonance GmbH, Aachen, Germany) followed by Prokinetic cobalt-chromium BMS (Biotronik AG, Bülach, Switzerland) versus implantation of Xience DES (Abbott Vascular, Santa Clara, CA). Because the safety of PEBs was still under investigation, a substudy was planned aiming to evaluate, using frequency-domain optical coherence tomography (FD-OCT), safety end points at 9-month follow-up among the first consecutive 30 patients enrolled in the PEB + BMS arm. All patients gave written informed consent. The trial was approved by our institutional ethics committee and was registered with ClinicalTrials.gov (NCT01637896). No extramural funding was used to support this work. Between January and October 2009, all consecutive patients with clinical indication for PCI of a de novo stenosis in a native coronary artery were randomized to the study. Clinical exclusion criteria were as follows: ST-segment elevation acute myocardial infarction; contraindication to prolonged dualantiplatelet therapy; allergy to aspirin, clopidogrel, or paclitaxel; and life expectancy of less than 1 year. Angiographic exclusion criteria were as follows: lesion length N 15 mm, reference vessel diameter (RVD) b 2.25 mm, chronic total occlusion, bifurcation lesion, and lesion located in the left main coronary segment. Randomization was performed in a 1:1 ratio by computerized, open-label assignment in consecutive blinded envelopes. A randomly permuted blocks method was used to generate the randomization list.
Study device The balloon used in this trial was the second-generation Elutax PEB, characterized by 2 layers of paclitaxel: the first on the inflated balloon and the second as a crystal powder (loaded dosage, 2 μg/mm 2). No eluting substance was present. Limited preclinical data were published (after the start of our trial), showing drug transfer to vessel wall in an animal model. 11 This device has now been replaced by the third-generation Elutax balloon, and it is not available in the market anymore.
Interventional procedure Percutaneous coronary intervention was performed according to institutional standards. All patients received a bolus of unfractionated heparin at dose of 70 IU/kg before starting the procedure. In patients randomized to PEB + BMS, the following interventional strategies were applied: predilatation with a conventional PCI balloon, PEB dilatation, and, finally, BMS
Liistro et al 921
implantation. For predilatation, care was taken to use a balloon shorter in length than the anticipated PEB, using low inflation pressure. To avoid geographical miss, the PEB-treated area was longer than the chosen stent and anatomical landmarks (bifurcations, side branches) were used. In case of uncertainty, dilatation with another PEB overlapping for at least 5 mm with the area previously treated with paclitaxel was performed to ensure drug delivery to the entire segment to be stented. Two inflations of at least 30 seconds were performed with the Elutax PEB, in agreement with the manufacturer's instructions. No postdilatation with PEB was allowed. In patients randomized to Xience V DES, predilatation was not mandatory. Stents were always implanted at inflation pressures N 12 atm. Stent postdilatation with a noncompliant balloon was performed only in case of suboptimal results judged by visual estimation. Combined antiplatelet therapy with aspirin (at least 100 mg daily) and clopidogrel 300-mg loading dose plus 75 mg daily was started at least 48 hours before the procedure and continued for at least 12 months in patients receiving DES and 3 months in those treated with PEB + BMS. Plasma concentrations of creatine kinase and its MB isoenzyme were systematically determined every 6 hours for 24 hours after the intervention. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Follow-up All patients were asked to return to outpatient clinic for evaluation by 1 of the investigators at 1, 6, and 9 months after hospital discharge. All patients with symptoms of chest pain were requested to come immediately to the outpatient clinic for clinical, electrocardiographic, and laboratory evaluation. Angiographic follow-up was scheduled at 9 months after procedure. The follow-up angiogram was obtained earlier if clinically indicated.
Angiographic analysis Coronary angiograms were analyzed by a semiautomated edge contour detection computer analysis system (QCA CMS version 4; Medis, Leiden, The Netherlands). All angiograms were analyzed in a random sequence by 2 experienced observers who were blinded to the clinical characteristics of patients. Reference vessel diameter, minimal lumen diameter (MLD), percentage diameter stenosis, and lesion length were measured before and at the end of the procedure and at follow-up. Measurements included the inner stenotic area, the stented area with “shoulder to shoulder” measurement (in-stent), and the total stented segment plus 5 mm of the proximal and distal length (in-segment). 12
Frequency-domain optical coherence tomography Frequency-domain optical coherence tomography image acquisition and analysis was performed as previously described. 13 Briefly, standard cross-sectional analysis measuring lumen, stent, and neointimal hyperplasia areas and volumes, plus quantitative strut-level analysis, were performed at 0.4-mm intervals (every other frame) along the entire target segment. The center of the luminal surface of the strut blooming was determined for each strut, and its distance to the lumen contour
American Heart Journal November 2013
922 Liistro et al
was calculated automatically to determine strut-level intimal thickness (SIT). Struts covered by tissue had positive SIT values, whereas uncovered or malapposed struts had negative SIT. The number of struts without coverage was counted for each frame analyzed, and the total number of frames with uncovered struts was recorded. Strut malapposition was determined when the negative value of SIT was higher than 100 μm (60-μm Prokinetic strut thickness, plus a correction factor of 40 μm to account for strut blooming). Struts were classified in 4 categories: embedded and covered, protruding and covered, uncovered apposed, and uncovered and malapposed. To evaluate the evidence of geographical mismatch, we compared the percentage net volume obstruction, calculated for the stent inflow and stent outflow (5-mm length) with the mean in-stent proliferation for the entire stent.
Definitions and outcome measures Major adverse cardiac events (MACEs) were defined as death from any cause, nonfatal reinfarction (myocardial infarction [MI]), and ischemia-driven target lesion revascularization (IDTLR) with re-PCI or coronary artery bypass graft surgery of the culprit lesion. Myocardial infarction was defined as the presence of new Q waves in ≥ 2 contiguous electrocardiogram leads or an elevation of creatine kinase or its MB isoenzyme to ≥ 3 times the upper limit of normal in 2 samples during hospitalization or to 2 times the upper limit of normal after discharge. Ischemia-driven target lesion revascularization was defined as any repeat PCI or aortocoronary bypass surgery due to lumen renarrowing within the stented segment associated with symptoms or objective signs of ischemia. Stent thrombosis was classified according to the Academic Research Consortium definition. 14 Binary restenosis at follow-up was defined as a stenosis occupying more than 50% of diameter. Restenosis was classified according to Mehran classification. 15
Study end points The primary end point of the study was the angiographic binary restenosis rate at 9 months. Secondary end points were IDTLR rate and MACE-free survival at 9 months.
Statistical analysis and power calculations A 5% rate of 9-month binary restenosis was projected in the Xience group. 16 Paclitaxel-eluting balloon was deemed not inferior to Xience if the upper limit of the 95% CI for the difference in restenosis rate was b 5%. Δ value (or upper limit of the accepted difference) was set at 5%. With a level of significance of .05 (1 sided), enrollment of 366 patients, accounting for a 5% dropout rate, was planned. The study was prematurely halted after enrollment of 125 patients (59 in the PEB group and 66 in the DES group) because of perceived excess of IDTLR in the PEB + BMS group. No formal interim analysis was performed, but the investigators considered unethical to continue the randomization of patients to PEB + BMS. With this sample size, a difference of about 15% with a power of 80% at a level of significance of .05 (2 tailed) could be demonstrated. Values are reported as numbers with relative percentage or SD. Nominal or ordinal variables were compared using the Fisher exact test for categorical data; continuous variables were compared using a t test. A 2-sided P value was considered
statistically significant if b .05. Kaplan–Meier estimates and logrank test survival methods were used to assess freedom from IDTLR and from MACE. Analyses were performed with SPSS software version 19 (IBM Corp, Somers, NY).
Results Study flow is reported in Figure 1. The clinical characteristics of the patients enrolled in the 2 study arms are reported in Table I. Procedural and angiographic characteristics of the patients are reported in Table II. Lesion and stent length were significantly higher in the DES group compared with the PEB + BMS group.Clinical events at 9-month follow-up are reported in Table III. One patient in the DES group developed an ST-elevation MI due to definite acute stent thrombosis 30 days after the procedure. This patient spontaneously discontinued antiplatelet treatment 2 weeks after hospital discharge. At 9-month follow-up, binary restenosis, either in-stent or in-segment, was significantly higher in the PEB+BMS compared to the DES group (Figure 2 & Table III), and an excess of IDTLR (4% vs. 25%; p=0.01) (Figure 3) and MACE (6% vs. 29%; p=0.01) was evident in the same arm. The first consecutive 30 of the 59 patients enrolled in the PEB + BMS arm of the study also underwent FD-OCT at follow-up. Of these, 3 patients were excluded because of evidence of restenosis needing extensive BA before FDOCT and 4 patients were excluded because of suboptimal images quality. The features of FD-OCT are summarized in Table IV. A total of 23 lesions in 23 patients were analyzed, for a total of 4,304 struts. Only 8 struts (0.2%), all in one single stent and at the same (proximal) stent edge, were found to be uncovered and malapposed, and 1 additional strut (in another patient) was found to be uncovered and apposed. A total of 67 struts (1.5%) were found covered but malapposed. Percentage net volume obstruction was 35% (26%-41%) (Figure 4). No evidence of geographical mismatch could be found because the percentage net volume obstruction was 40% (24%-47%) at stent inflow and 36% (22%-39%) at stent outflow, with both percentages not different from the mean value (P value not significant).
Discussion The aim of our trial was to compare the efficacy of a strategy of predilatation with a second-generation PEB followed by systematic BMS, with a strategy of implantation of an everolimus-eluting stent. The decision to interrupt the study with only 125 enrolled patients was based on a perceived excess of IDTLR in the PEB+BMS group, observed by all investigators and subsequently confirmed at the end of follow-up, where we found significantly increased restenosis and IDTLR rates in the PEB+BMS arm. Indeed, restenosis in the latter group appeared similar to the rate found in the BMS arm of
American Heart Journal Volume 166, Number 5
Liistro et al 923
Figure 1
Study flow.
Table I. Baseline clinical characteristics
Table II. Procedural and angiographic characteristics
PEB + BMS (n = 59) DES (n = 66) P Male sex, n (%) Age (y), mean ± SD) Current smoker, n (%) Diabetes, n (%) Family history of CAD, n (%) Hypertension, n (%) Hypercholesterolemia, n (%) Previous MI, n (%) NSTEACS, n (%) Creatinine (mg/dL) LVEF (%)
49 (83) 66 ± 11 15 (25) 7 (12) 7 (12) 22 (37) 6 (10) 4 (7) 15 (25) 1.1 ± 0.2 56.8 ± 11
58 (87) 65 ± 12 23 (34) 10 (15) 9 (13) 28 (42) 10 (16) 6 (9) 18 (27) 1.0 ± 0.1 58.5 ± 11
.1 .8 .3 .8 .9 .7 .5 .8 .8 .7 .1
Data presented are numbers and relative percentages (%) and mean values ± SD. CAD, Coronary artery disease; NSTEACS, non–ST elevation acute coronary syndrome; LVEF, left ventricular ejection fraction.
several studies comparing BMS vs. DES, 17,18 and neointimal volume was also comparable to historical BMS data. 13 In addition to the absence of strut malapposition in the PEB group, these data suggest an almost total lack of efficacy by second-generation Elutax PEB prior to systematic BMS implantation. Our study has to be firstly compared with the data stemming from the Paclitaxel-Eluting PTCA-Catheter in Coronary Artery Disease (PEPCAD) program, which used the SeQuent Please (B Braun Melsungen AG, Vascular Systems, Berlin, Germany) balloon, with a hydrophilic
Culprit vessel LAD, n (%) LCX, n (%) RCA, n (%) Lesion length (mm), mean ± SD RVD (mm), mean ± SD Basal MLD (mm), mean ± SD Final MLD (mm), mean ± SD Stent diameter (mm), mean ± SD Stent length (mm), mean ± SD Direct stenting, n (%) Stent postdilatation, n (%) Complete revascularization, n (%) Additionalstenting, n (%) Procedural success, n (%)
PEB + BMS (n = 59)
DES (n = 66)
P
26 (44) 12 (20) 21 (35) 10.7 ± 2.15 2.85 ± 0.52 0.79 ± 0.42 2.89 ± 0.53 2.98 ± 0.31 15.5 ± 5.24 0 (0) 20 (33) 48 (81) 3 (5) 59 (100)
30 (33) 11 (16) 25 (37) 12.5 ± 5.5 2.77 ± 0.53 0.75 ± 0.40 2.77 ± 0.39 2.86 ± 0.38 18.6 ± 7.10 45 (68) 25 (41) 52 (78) 4 (6) 66 (100)
.6 .7 .9 .03 .3 .5 .1 .07 .01 .3 .6 .9 1.0
Data presented are numbers and relative percentages (%) and mean values ± SD. LAD, Left anterior descending; LCX, left circumflex; RCA, right coronary artery.
iopromide-derived carrier and a concentration of paclitaxel of 3 μg/mm 2 at balloon surface. In particular, in the PEPCAD III study 19 comparing the Coroflex DEBlue system (hybrid of Coroflex BMS premounted onto a SeQuent Please PEB) vs Cypher sirolimus-eluting stent (Cordis Corporation, Miami Lakes, FL) in patients with a single de novo lesion, PEB-treated patients showed almost 3 times higher in-stent late lumen loss, translating to
American Heart Journal November 2013
924 Liistro et al
Table III. Clinical and angiographic outcome
Death, n (%) MI, n (%) TVR, n (%) IDTLR, n (%) MACE, n (%) RVD (mm), mean ± SD MLD (mm), mean ± SD Late loss (mm), mean ± SD Binary restenosis In stent, n (%) In segment, n (%) Restenosis pattern Mehran classes I-II, n (%) Mehran class III, n (%) Mehran class IV, n (%)
Figure 2
PEB + BMS (n = 59)
DES (n = 66)
P
0 (0) 0 (0) 17 (29) 15 (25) 17 (29) 2.87 ± 0.32 1.77 ± 1.0 1.14 ± 1.0
0 (0) 1 (1.5) 4 (6) 3 (4) 4 (6) 2.89 ± 0.43 2.41 ± 0.70 0.34 ± 0.70
1.0 .5 .01 .009 .01 .3 .01 .001
10 (17) 15 (25)
2 (3) 3 (4)
.01 .009 .78
7 (12) 5 (8) 3 (5)
1 (1) 1 (1) 1 (1)
Data presented are numbers and relative percentages (%) and mean values ± SD. TVR, target vessel revascularization.
significantly more revascularizations. Recently, an IVUS substudy of the PEPCAD III has been published, confirming higher neointimal hyperplasia in the PEB + BMS group. 20 In addition, in the small PEPCAD IV study, 6 comparing the Coroflex DEBlue system with paclitaxeleluting Taxus stent (Boston Scientific, Natick, MA) in diabetic patients, late lumen loss was similar in the 2 studied groups. Overall, our results corroborate the lack of efficacy of the PEB + BMS combination, extending this observation to a larger group treated with a different PEB. Of note, several insights can be made from our data. First, the PEPCAD III study is still unpublished as full-text paper, raising the possibility of reporting bias, the tendency not to publish clinical trials with negative results, particularly associated with industry-funded studies. 21 Second, the combination device used in the PEPCAD program, while mitigating the potential issue of geographical mismatch, only allowed PEB postdilatation. Other investigators, however, have shown that the sequence of application (PEB first versus BMS first) does not influence the outcome. 22,23 Another possible comparator is the Diabetic Argentina Registry, in which the Dior (Eurocor GmbH, Bonn, Germany) PEB, with a paclitaxel-shellac resin (1:1) coating in layers, showed a low target lesion revascularization (TLR) rate of 6.6%. The authors enrolled 92 patients with diabetes mellitus who underwent PEB angioplasty, followed by BMS in 96% of the cases, and compared with historical controls treated with DES (n= 129 pts) or BMS (n=96 pts). Among the many limitations of this study, however, are the lack of adjustment for potential confouders and the low overall differences between groups in terms of revascularization. 24 The recent drug-eluting balloon in acute ST-elevation MI DEBAMI compared the Dior PEB plus BMS vs BMS vs DES in primary PCI. 25 In this study, predilatation with PEB did
Rate of in-stent and in-segment restenosis and of IDTLR in the 2 study groups.
not reduce restenosis compared with BMS. 25 Frequencydomain optical coherence tomography revealed some drug effect induced by PEB, with higher rates of uncovered and malapposed struts compared with BMS, but not to the point of inhibiting neointimal hyperplasia. 25 Finally, 2 very recent meta-analyses have confirmed the lack of efficacy of PEB + BMS strategy compared with DES, although both have shown important heterogeneity, as the employed devices (balloon plus stent) were different in each trial. 26,27 Several reasons can be claimed to explain the lack of efficacy of PEB + (systematic) BMS. First, it is reasonable that the paclitaxel released by PEB can prevent restenosis when vessel injury is confined to BA, but might not be able to negotiate the more powerful intimal response derived from stent implantation. 28 Moreover, the use of a polymer-coating technology in DES 29 is associated with gradual drug release over time, whereas paclitaxelis generally released by PEB in a single “shot.” Paclitaxel bioavailability in the vessel wall also seems to be influenced by the specific PEB technology. 30 Importantly a side-by-side comparison in a porcine model of various PEB demonstrated marked differences in late luminal loss. 30
Limitations First, this trial was prematurely stopped and we are fully aware that our findings should only be interpreted as exploratory. Despite the lack of an independent safety
American Heart Journal Volume 166, Number 5
Liistro et al 925
Figure 3
Figure 4
Kaplan-Meier curves of cumulative incidence at 9 months of IDTLR for PEB + BMS (circles) and for DES (triangle).
Table IV. Clinical, angiographic, and FD-OCT data (n = 24) Clinical Age (y), median (IQR) Male sex, n (%) Current smokers, n (%) Diabetes, n (%) Family history of CAD, n (%) Hypertension, n (%) Dyslipidemia, n (%) Target vessel LAD, n (%) LCx, n (%) RCA, n (%) Stent length (mm), median (IQR) Stent diameter (mm), median (IQR) FD-OCT cross-section analysis Minimal lumen area (mm 2) Minimal stent area (mm 2) Maximal neointimal area (mm 2) Lumen volume (mm 3) Stent volume (mm 3) Neointimal volume (mm 3) Net volume obstruction (%) FD-OCT strut-level analysis Total no. of struts analyzed, n Covered embedded struts per lesion, n (%) Covered protruding struts per lesion, n (%) Uncovered struts per lesion, n (%) Malapposed struts per lesion, n (%)
66 (62-76) 21 (87.5) 10 (41.7) 5 (20.8) 4 (16.7) 13 (54.2) 10 (41.7) 10 (41.7) 6 (25.0) 8 (33.3) 15.0 (13.0-18.0) 3.00 (2.75-3.50) 4.0 (2.3-4.8) 7.0 (5.9-8.5) 3.6 (2.4-4.4) 81 (59.8-101.5) 116.9 (86.4-145.6) 37.9 (34.5-57.8) 35 (26-41) 4304 99 (98-100) 1.5 (0.5-1.8) 0 (0-0) 0 (0-0)
IQR, Interquartile range; CAD, coronary artery disease LAD, left anterior descending; LCx, left circumflex; RCA, right coronary artery.
In this frequency-domain optical coherence tomography image, an example of the typical thick neointimal tissue found at 9 months after PEB + BMS is shown. A single malapposed (but covered) strut is visible, more clearly in the magnified view (upper left panel, dotted line indicates the same strut shadowing in both normal and magnified view).
present in continuing a trial with evidence of a clear inferiority in one of the randomized arms. Second, the high restenosis rate observed in our study might potentially be related to geographical miss. However, stent length was always inferior to the segment treated with PEB. Of note, no evidence of geographical miss was observed in the 24 patients who underwent FDOCT imaging at follow-up. Third, friction between PEB and stenosis surfaces and loss of drug from the balloon are potential drawbacks of PEB technology. However, all lesions were predilated with conventional balloons avoiding extensive contact with the vessel wall during lesion crossing and before deployment. Fourth, the single-center nature of our trial and the absence of a core laboratory for restenosis evaluation must be acknowledged. Last, no FD-OCT follow-up was performed in the DES group. However, financial constraints were present in running a non–industry-funded trial, and the reason for performing FD-OCT was mainly to provide safety data in the PEB + BMS group.
Conclusion monitor or an adjudication committee, we decided to halt the study, after extensive internal discussion, because of a perceived excess of IDTLR in the PEB + BMS group. This has reduced the power of our study and the general applicability of our results. However, ethical issues were
In this study, PEB + BMS was significantly inferior to DES. The development of more sophisticated PEB technologies with different drug carriers capable to enhance drug bioavailability and permanence in the vessel wall will be essential for future studies.
American Heart Journal November 2013
926 Liistro et al
Disclosures None of the Authors has any conflict of interest related to the Manuscript.
17.
References
18.
1. Bangalore S, Kumar S, Fusaro M, et al. Short and long-term outcomes with drug eluting and bare metal coronary stents: a mixed treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation 2012;125:2873-91. 2. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745-54. 3. Speck U, Cremers B, Kelsch B, et al. Do pharmacokinetics explain persistent restenosis inhibition by a single dose of paclitaxel? Circ Cardiovasc Interv 2012;5:392-400. 4. Scheller B, Speck U, Abramjuk C, et al. Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. Circulation 2004;110:810-4. 5. Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drugeluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol 2012;59:1377-82. 6. Ali RM, Degenhardt R, Zambahari R, et al. Paclitaxel-eluting balloon angioplasty and cobalt-chromium stents versus conventional angioplasty and paclitaxel-eluting stents in the treatment of native coronary artery stenoses in patients with diabetes mellitus. EuroIntervention 2011(Suppl K):K83-92. 7. Micari A, Cioppa A, Vadalà G, et al. A new paclitaxel-eluting balloon for angioplasty of femoropopliteal obstructions: acute and midterm results. EuroIntervention 2011(Suppl K):K77-82. 8. Liistro F, Porto I, Grotti S, et al. Drug-eluting balloon angioplasty for carotid in-stent restenosis. J Endovasc Ther 2012;19:729-33. 9. Black AJ, Namay DL, Niederman AL, et al. Tear or dissection after coronary angioplasty. Morphologic correlates of an ischemic complication. Circulation 1989;79:1035-42. 10. Mintz GS, Popma JJ, Pichard AD, et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996;94:35-43. 11. Ruebben ABJ, Weiss N. Drug-eluting balloon analysis. Interv Cardiol (Touch briefings) 2010;4:74-6. 12. Garrone P, Biondi-Zoccai G, Salvetti I, et al. Quantitative coronary angiography in the current era: principles and applications. J Interv Cardiol 2009;22:527-36. 13. Guagliumi G, Costa MA, Sirbu V, et al. Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Circulation 2011;123:274-81. 14. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51. 15. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of instent restenosis: classification and implications for long-term outcome. Circulation 1999;100:1872-8. 16. Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
coronary artery disease: a randomized trial. JAMA 2008;299: 1903-13. Roukoz H, Bavry AA, Sarkees ML, et al. Comprehensive metaanalysis on drug-eluting stents versus bare-metal stents during extended follow-up. Am J Med 2009;122:581.e1-581.e10. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356:1030-9. Pöss J, Jacobshagen C, Ukena C, et al. Hotlines and clinical trial updates presented at the German Cardiac Society Meeting 2010: FAIR-HF, CIPAMI, LIPSIA-NSTEMI, Handheld-BNP, PEPCAD III, remote ischaemic conditioning, CERTIFY, PreSCD-II, German Myocardial Infarction Registry, DiaRegis. Clin Res Cardiol 2010;99:411-7. Fischer D, Scheller B, Schafer A, et al. Paclitaxcel-coated balloon plus bare metal stent vs. sirolimus-eluting stent in de novo lesions: an IVUS study. EuroIntervention 2012;8:450-5. Bourgeois FT, Murthy S, Mandl KD. Outcome reporting among drug trials registered in ClinicalTrials.gov. Ann Intern Med 2010;153: 158-66. Gutiérrez-Chico JL, van Geuns RJ, Koch KT, et al. Paclitaxel-coated balloon in combination with bare metal stent for treatment of de novo coronary lesions: an optical coherence tomography first-in-human randomised trial, balloon first vs. stent first. EuroIntervention 2011;7: 711-22. Poerner TC, Otto S, Janiak F, et al. A prospective randomized study using optical coherence tomography to assess endothelial coverage and neointimal proliferation at 6 months after implantation of a coronary everolimus-eluting stent compared with bare metal stent postdilated with a paclitaxel-eluting balloon (OCTOPUS trial). J Am Coll Cardiol 2012;59:E281. Mieres J, Fernandez-Pereira C, Risau G, et al. One-year outcome of patients with diabetes mellitus after percutaneous coronary intervention with three different revascularization strategies: results from the Diabetic Argentina Registry (DEAR). Cardiovasc Revasc Med 2012;13:265-71. Belkacemi A, Agostoni P, Nathoe HM, et al. First results of the DEBAMI (Drug Eluting Balloon in Acute ST-Segment Elevation Myocardial Infarction) trial: a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drugeluting stent in primary percutaneous coronary intervention with 6month angiographic, intravascular, functional, and clinical outcomes. J Am Coll Cardiol 2012;59:2327-37. Frohlich GM, Lansky AJ, Ko DT, et al. Drug eluting balloons for de novo coronary lesions—a systematic review and meta-analysis. BMC Med 2013;11:123. Zhang T, Sun S, Shen L, et al. Drug-eluting balloons for de novo coronary artery disease: a meta-analysis of angiographic and clinical data. Catheter Cardiovasc Interv 2013;22:1-10. Speck U, Scheller B, Rutsch W, et al. Local drug delivery—the early Berlin experience: single drug administration versus sustained release. EuroIntervention 2011(Suppl K):K17-22. Lansky AJ, Costa RA, Mintz GS, et al. Non–polymer-based paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation 2004;109:1948-54. Radke PW, Joner M, Joost A, et al. Vascular effects of paclitaxel following drug-eluting balloon angioplasty in a porcine coronary model: the importance of excipients. EuroIntervention 2011;7: 730-7.
Background Paclitaxel-eluting balloons (PEBs) are a promising alternative to drug-eluting stent (DES) in the treatment of coronary stenoses. The aim of our study was to compare the 9-month restenosis rates of a strategy of predilatation with PEB followed by bare-metal CoCr stent (PEB + BMS group) versus implantation of everolimus DES (DES group). Methods This randomized, single-center study planned to enroll 366 patients with stable angina (183 patients per arm) undergoing percutaneous coronary intervention of a de novo, native coronary artery stenosis ≤ 15 mm in length. Primary end point, in a noninferiority study design, was 9-month binary angiographic restenosis. A frequency-domain optical coherence tomography substudy investigated the percentage of uncovered stent struts per lesion, the percentage of malapposed/ uncovered struts per lesion, and the percentage of net volume obstruction at 9-month follow-up among the first consecutive 30 patients enrolled in the PEB + BMS group. Results
The study was prematurely halted after enrollment of 125 patients, 59 in the PEB + BMS group and 66 in the DES group, because of excess of ischemia-driven target lesion revascularization in the PEB + BMS group. When all the enrolled patients completed their follow-up, IDLTR rates were 14% in the PEB + BMS versus 2% in DES group (P = .001). Binary restenosis, either in-stent or in-segment, was significantly higher in the PEB + BMS compared with DES group (17% vs 3% [P = .01] and 25% vs 4% [P = .009] respectively). Frequency-domain optical coherence tomography demonstrated important neointimal regrowth in the PEB + BMS group, similar to historical BMS data.
Conclusion In the treatment of de novo coronary stenosis, a strategy of predilatation with PEB before BMS implantation was significantly inferior to implantation of an everolimus DES stent in terms of 9-month target lesion revascularization. Frequency-domain optical coherence tomography data confirm the lack of efficacy of this strategy. (Am Heart J 2013;166:920-6.)
In the last 10 years, drug-eluting stents (DESs) have progressively replaced bare-metal stents (BMSs) in coronary revascularization procedures. 1 Dependency on long-term dual-antiplatelet therapy, however, has become a major issue for patients receiving these
From the aCardiovascular and Neurologic Department, San Donato Hospital, Arezzo, Italy, and bDepartment of Cardiovascular Diseases, University of Siena, Le Scotte Hospital, Siena, Italy. Presented, in part, at the Transcatheter Cardiovascular Therapeutics, November 2011, San Francisco, CA, and published in an abstract form (J Am Coll Cardiol. 2011;58(Suppl B):B5). Submitted March 8, 2013; accepted August 7, 2013. Reprint requests: Italo Porto, MD, PhD, Cardiovascular and Neurologic Department, San Donato Hospital, Via Pietro Nenni 22, 52100 Arezzo, Italy. E-mail: [email protected] 0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2013.08.023
devices. 2 Recently, paclitaxel-eluting balloons (PEBs) have emerged as a potential alternative to DES. Paclitaxel was identified as the primary drug for balloon coating because of its rapid release and prolonged retention. 3 Paclitaxel-eluting balloon technology demonstrated safety and efficacy in preclinical 4 and in randomized trials for patients with coronary in-stent restenosis, 5 de novo lesions in small vessels, 6 lesions in the superficial femoral artery, 7 and, recently, also for carotid in-stent restenosis. 8 Potential advantages of PEB over DES include the following: (1) homogenous drug transfer to the entire vessel wall; (2) rapid, sustained release of high concentrations of the drug in the vessel wall; and (3) absence of polymer. 3 Elastic recoil and flow-limiting dissections, 9,10 however, the Achilles' heel of balloon angioplasty (BA), are also potential limitations of PEB, and in the absence of the mechanical scaffolding provided by stent struts, PEB angioplasty of complex coronary lesions is not
American Heart Journal Volume 166, Number 5
recommended. We elected to compare, in terms of a 9month restenosis, an interventional strategy based on lesion predilatation with PEB followed by cobalt-chromium BMS implantation with a strategy of DES implantation in patients undergoing coronary intervention for a de novo coronary stenosis.
Materials and methods Patient population and study design The study was designed as a prospective, randomized, singlecenter, investigator-initiated, single-blind study. The aim, in patients undergoing percutaneous coronary intervention (PCI), was to compare the 9-month restenosis rate of a strategy of predilatation with Elutax PEB (Aachen Resonance GmbH, Aachen, Germany) followed by Prokinetic cobalt-chromium BMS (Biotronik AG, Bülach, Switzerland) versus implantation of Xience DES (Abbott Vascular, Santa Clara, CA). Because the safety of PEBs was still under investigation, a substudy was planned aiming to evaluate, using frequency-domain optical coherence tomography (FD-OCT), safety end points at 9-month follow-up among the first consecutive 30 patients enrolled in the PEB + BMS arm. All patients gave written informed consent. The trial was approved by our institutional ethics committee and was registered with ClinicalTrials.gov (NCT01637896). No extramural funding was used to support this work. Between January and October 2009, all consecutive patients with clinical indication for PCI of a de novo stenosis in a native coronary artery were randomized to the study. Clinical exclusion criteria were as follows: ST-segment elevation acute myocardial infarction; contraindication to prolonged dualantiplatelet therapy; allergy to aspirin, clopidogrel, or paclitaxel; and life expectancy of less than 1 year. Angiographic exclusion criteria were as follows: lesion length N 15 mm, reference vessel diameter (RVD) b 2.25 mm, chronic total occlusion, bifurcation lesion, and lesion located in the left main coronary segment. Randomization was performed in a 1:1 ratio by computerized, open-label assignment in consecutive blinded envelopes. A randomly permuted blocks method was used to generate the randomization list.
Study device The balloon used in this trial was the second-generation Elutax PEB, characterized by 2 layers of paclitaxel: the first on the inflated balloon and the second as a crystal powder (loaded dosage, 2 μg/mm 2). No eluting substance was present. Limited preclinical data were published (after the start of our trial), showing drug transfer to vessel wall in an animal model. 11 This device has now been replaced by the third-generation Elutax balloon, and it is not available in the market anymore.
Interventional procedure Percutaneous coronary intervention was performed according to institutional standards. All patients received a bolus of unfractionated heparin at dose of 70 IU/kg before starting the procedure. In patients randomized to PEB + BMS, the following interventional strategies were applied: predilatation with a conventional PCI balloon, PEB dilatation, and, finally, BMS
Liistro et al 921
implantation. For predilatation, care was taken to use a balloon shorter in length than the anticipated PEB, using low inflation pressure. To avoid geographical miss, the PEB-treated area was longer than the chosen stent and anatomical landmarks (bifurcations, side branches) were used. In case of uncertainty, dilatation with another PEB overlapping for at least 5 mm with the area previously treated with paclitaxel was performed to ensure drug delivery to the entire segment to be stented. Two inflations of at least 30 seconds were performed with the Elutax PEB, in agreement with the manufacturer's instructions. No postdilatation with PEB was allowed. In patients randomized to Xience V DES, predilatation was not mandatory. Stents were always implanted at inflation pressures N 12 atm. Stent postdilatation with a noncompliant balloon was performed only in case of suboptimal results judged by visual estimation. Combined antiplatelet therapy with aspirin (at least 100 mg daily) and clopidogrel 300-mg loading dose plus 75 mg daily was started at least 48 hours before the procedure and continued for at least 12 months in patients receiving DES and 3 months in those treated with PEB + BMS. Plasma concentrations of creatine kinase and its MB isoenzyme were systematically determined every 6 hours for 24 hours after the intervention. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Follow-up All patients were asked to return to outpatient clinic for evaluation by 1 of the investigators at 1, 6, and 9 months after hospital discharge. All patients with symptoms of chest pain were requested to come immediately to the outpatient clinic for clinical, electrocardiographic, and laboratory evaluation. Angiographic follow-up was scheduled at 9 months after procedure. The follow-up angiogram was obtained earlier if clinically indicated.
Angiographic analysis Coronary angiograms were analyzed by a semiautomated edge contour detection computer analysis system (QCA CMS version 4; Medis, Leiden, The Netherlands). All angiograms were analyzed in a random sequence by 2 experienced observers who were blinded to the clinical characteristics of patients. Reference vessel diameter, minimal lumen diameter (MLD), percentage diameter stenosis, and lesion length were measured before and at the end of the procedure and at follow-up. Measurements included the inner stenotic area, the stented area with “shoulder to shoulder” measurement (in-stent), and the total stented segment plus 5 mm of the proximal and distal length (in-segment). 12
Frequency-domain optical coherence tomography Frequency-domain optical coherence tomography image acquisition and analysis was performed as previously described. 13 Briefly, standard cross-sectional analysis measuring lumen, stent, and neointimal hyperplasia areas and volumes, plus quantitative strut-level analysis, were performed at 0.4-mm intervals (every other frame) along the entire target segment. The center of the luminal surface of the strut blooming was determined for each strut, and its distance to the lumen contour
American Heart Journal November 2013
922 Liistro et al
was calculated automatically to determine strut-level intimal thickness (SIT). Struts covered by tissue had positive SIT values, whereas uncovered or malapposed struts had negative SIT. The number of struts without coverage was counted for each frame analyzed, and the total number of frames with uncovered struts was recorded. Strut malapposition was determined when the negative value of SIT was higher than 100 μm (60-μm Prokinetic strut thickness, plus a correction factor of 40 μm to account for strut blooming). Struts were classified in 4 categories: embedded and covered, protruding and covered, uncovered apposed, and uncovered and malapposed. To evaluate the evidence of geographical mismatch, we compared the percentage net volume obstruction, calculated for the stent inflow and stent outflow (5-mm length) with the mean in-stent proliferation for the entire stent.
Definitions and outcome measures Major adverse cardiac events (MACEs) were defined as death from any cause, nonfatal reinfarction (myocardial infarction [MI]), and ischemia-driven target lesion revascularization (IDTLR) with re-PCI or coronary artery bypass graft surgery of the culprit lesion. Myocardial infarction was defined as the presence of new Q waves in ≥ 2 contiguous electrocardiogram leads or an elevation of creatine kinase or its MB isoenzyme to ≥ 3 times the upper limit of normal in 2 samples during hospitalization or to 2 times the upper limit of normal after discharge. Ischemia-driven target lesion revascularization was defined as any repeat PCI or aortocoronary bypass surgery due to lumen renarrowing within the stented segment associated with symptoms or objective signs of ischemia. Stent thrombosis was classified according to the Academic Research Consortium definition. 14 Binary restenosis at follow-up was defined as a stenosis occupying more than 50% of diameter. Restenosis was classified according to Mehran classification. 15
Study end points The primary end point of the study was the angiographic binary restenosis rate at 9 months. Secondary end points were IDTLR rate and MACE-free survival at 9 months.
Statistical analysis and power calculations A 5% rate of 9-month binary restenosis was projected in the Xience group. 16 Paclitaxel-eluting balloon was deemed not inferior to Xience if the upper limit of the 95% CI for the difference in restenosis rate was b 5%. Δ value (or upper limit of the accepted difference) was set at 5%. With a level of significance of .05 (1 sided), enrollment of 366 patients, accounting for a 5% dropout rate, was planned. The study was prematurely halted after enrollment of 125 patients (59 in the PEB group and 66 in the DES group) because of perceived excess of IDTLR in the PEB + BMS group. No formal interim analysis was performed, but the investigators considered unethical to continue the randomization of patients to PEB + BMS. With this sample size, a difference of about 15% with a power of 80% at a level of significance of .05 (2 tailed) could be demonstrated. Values are reported as numbers with relative percentage or SD. Nominal or ordinal variables were compared using the Fisher exact test for categorical data; continuous variables were compared using a t test. A 2-sided P value was considered
statistically significant if b .05. Kaplan–Meier estimates and logrank test survival methods were used to assess freedom from IDTLR and from MACE. Analyses were performed with SPSS software version 19 (IBM Corp, Somers, NY).
Results Study flow is reported in Figure 1. The clinical characteristics of the patients enrolled in the 2 study arms are reported in Table I. Procedural and angiographic characteristics of the patients are reported in Table II. Lesion and stent length were significantly higher in the DES group compared with the PEB + BMS group.Clinical events at 9-month follow-up are reported in Table III. One patient in the DES group developed an ST-elevation MI due to definite acute stent thrombosis 30 days after the procedure. This patient spontaneously discontinued antiplatelet treatment 2 weeks after hospital discharge. At 9-month follow-up, binary restenosis, either in-stent or in-segment, was significantly higher in the PEB+BMS compared to the DES group (Figure 2 & Table III), and an excess of IDTLR (4% vs. 25%; p=0.01) (Figure 3) and MACE (6% vs. 29%; p=0.01) was evident in the same arm. The first consecutive 30 of the 59 patients enrolled in the PEB + BMS arm of the study also underwent FD-OCT at follow-up. Of these, 3 patients were excluded because of evidence of restenosis needing extensive BA before FDOCT and 4 patients were excluded because of suboptimal images quality. The features of FD-OCT are summarized in Table IV. A total of 23 lesions in 23 patients were analyzed, for a total of 4,304 struts. Only 8 struts (0.2%), all in one single stent and at the same (proximal) stent edge, were found to be uncovered and malapposed, and 1 additional strut (in another patient) was found to be uncovered and apposed. A total of 67 struts (1.5%) were found covered but malapposed. Percentage net volume obstruction was 35% (26%-41%) (Figure 4). No evidence of geographical mismatch could be found because the percentage net volume obstruction was 40% (24%-47%) at stent inflow and 36% (22%-39%) at stent outflow, with both percentages not different from the mean value (P value not significant).
Discussion The aim of our trial was to compare the efficacy of a strategy of predilatation with a second-generation PEB followed by systematic BMS, with a strategy of implantation of an everolimus-eluting stent. The decision to interrupt the study with only 125 enrolled patients was based on a perceived excess of IDTLR in the PEB+BMS group, observed by all investigators and subsequently confirmed at the end of follow-up, where we found significantly increased restenosis and IDTLR rates in the PEB+BMS arm. Indeed, restenosis in the latter group appeared similar to the rate found in the BMS arm of
American Heart Journal Volume 166, Number 5
Liistro et al 923
Figure 1
Study flow.
Table I. Baseline clinical characteristics
Table II. Procedural and angiographic characteristics
PEB + BMS (n = 59) DES (n = 66) P Male sex, n (%) Age (y), mean ± SD) Current smoker, n (%) Diabetes, n (%) Family history of CAD, n (%) Hypertension, n (%) Hypercholesterolemia, n (%) Previous MI, n (%) NSTEACS, n (%) Creatinine (mg/dL) LVEF (%)
49 (83) 66 ± 11 15 (25) 7 (12) 7 (12) 22 (37) 6 (10) 4 (7) 15 (25) 1.1 ± 0.2 56.8 ± 11
58 (87) 65 ± 12 23 (34) 10 (15) 9 (13) 28 (42) 10 (16) 6 (9) 18 (27) 1.0 ± 0.1 58.5 ± 11
.1 .8 .3 .8 .9 .7 .5 .8 .8 .7 .1
Data presented are numbers and relative percentages (%) and mean values ± SD. CAD, Coronary artery disease; NSTEACS, non–ST elevation acute coronary syndrome; LVEF, left ventricular ejection fraction.
several studies comparing BMS vs. DES, 17,18 and neointimal volume was also comparable to historical BMS data. 13 In addition to the absence of strut malapposition in the PEB group, these data suggest an almost total lack of efficacy by second-generation Elutax PEB prior to systematic BMS implantation. Our study has to be firstly compared with the data stemming from the Paclitaxel-Eluting PTCA-Catheter in Coronary Artery Disease (PEPCAD) program, which used the SeQuent Please (B Braun Melsungen AG, Vascular Systems, Berlin, Germany) balloon, with a hydrophilic
Culprit vessel LAD, n (%) LCX, n (%) RCA, n (%) Lesion length (mm), mean ± SD RVD (mm), mean ± SD Basal MLD (mm), mean ± SD Final MLD (mm), mean ± SD Stent diameter (mm), mean ± SD Stent length (mm), mean ± SD Direct stenting, n (%) Stent postdilatation, n (%) Complete revascularization, n (%) Additionalstenting, n (%) Procedural success, n (%)
PEB + BMS (n = 59)
DES (n = 66)
P
26 (44) 12 (20) 21 (35) 10.7 ± 2.15 2.85 ± 0.52 0.79 ± 0.42 2.89 ± 0.53 2.98 ± 0.31 15.5 ± 5.24 0 (0) 20 (33) 48 (81) 3 (5) 59 (100)
30 (33) 11 (16) 25 (37) 12.5 ± 5.5 2.77 ± 0.53 0.75 ± 0.40 2.77 ± 0.39 2.86 ± 0.38 18.6 ± 7.10 45 (68) 25 (41) 52 (78) 4 (6) 66 (100)
.6 .7 .9 .03 .3 .5 .1 .07 .01 .3 .6 .9 1.0
Data presented are numbers and relative percentages (%) and mean values ± SD. LAD, Left anterior descending; LCX, left circumflex; RCA, right coronary artery.
iopromide-derived carrier and a concentration of paclitaxel of 3 μg/mm 2 at balloon surface. In particular, in the PEPCAD III study 19 comparing the Coroflex DEBlue system (hybrid of Coroflex BMS premounted onto a SeQuent Please PEB) vs Cypher sirolimus-eluting stent (Cordis Corporation, Miami Lakes, FL) in patients with a single de novo lesion, PEB-treated patients showed almost 3 times higher in-stent late lumen loss, translating to
American Heart Journal November 2013
924 Liistro et al
Table III. Clinical and angiographic outcome
Death, n (%) MI, n (%) TVR, n (%) IDTLR, n (%) MACE, n (%) RVD (mm), mean ± SD MLD (mm), mean ± SD Late loss (mm), mean ± SD Binary restenosis In stent, n (%) In segment, n (%) Restenosis pattern Mehran classes I-II, n (%) Mehran class III, n (%) Mehran class IV, n (%)
Figure 2
PEB + BMS (n = 59)
DES (n = 66)
P
0 (0) 0 (0) 17 (29) 15 (25) 17 (29) 2.87 ± 0.32 1.77 ± 1.0 1.14 ± 1.0
0 (0) 1 (1.5) 4 (6) 3 (4) 4 (6) 2.89 ± 0.43 2.41 ± 0.70 0.34 ± 0.70
1.0 .5 .01 .009 .01 .3 .01 .001
10 (17) 15 (25)
2 (3) 3 (4)
.01 .009 .78
7 (12) 5 (8) 3 (5)
1 (1) 1 (1) 1 (1)
Data presented are numbers and relative percentages (%) and mean values ± SD. TVR, target vessel revascularization.
significantly more revascularizations. Recently, an IVUS substudy of the PEPCAD III has been published, confirming higher neointimal hyperplasia in the PEB + BMS group. 20 In addition, in the small PEPCAD IV study, 6 comparing the Coroflex DEBlue system with paclitaxeleluting Taxus stent (Boston Scientific, Natick, MA) in diabetic patients, late lumen loss was similar in the 2 studied groups. Overall, our results corroborate the lack of efficacy of the PEB + BMS combination, extending this observation to a larger group treated with a different PEB. Of note, several insights can be made from our data. First, the PEPCAD III study is still unpublished as full-text paper, raising the possibility of reporting bias, the tendency not to publish clinical trials with negative results, particularly associated with industry-funded studies. 21 Second, the combination device used in the PEPCAD program, while mitigating the potential issue of geographical mismatch, only allowed PEB postdilatation. Other investigators, however, have shown that the sequence of application (PEB first versus BMS first) does not influence the outcome. 22,23 Another possible comparator is the Diabetic Argentina Registry, in which the Dior (Eurocor GmbH, Bonn, Germany) PEB, with a paclitaxel-shellac resin (1:1) coating in layers, showed a low target lesion revascularization (TLR) rate of 6.6%. The authors enrolled 92 patients with diabetes mellitus who underwent PEB angioplasty, followed by BMS in 96% of the cases, and compared with historical controls treated with DES (n= 129 pts) or BMS (n=96 pts). Among the many limitations of this study, however, are the lack of adjustment for potential confouders and the low overall differences between groups in terms of revascularization. 24 The recent drug-eluting balloon in acute ST-elevation MI DEBAMI compared the Dior PEB plus BMS vs BMS vs DES in primary PCI. 25 In this study, predilatation with PEB did
Rate of in-stent and in-segment restenosis and of IDTLR in the 2 study groups.
not reduce restenosis compared with BMS. 25 Frequencydomain optical coherence tomography revealed some drug effect induced by PEB, with higher rates of uncovered and malapposed struts compared with BMS, but not to the point of inhibiting neointimal hyperplasia. 25 Finally, 2 very recent meta-analyses have confirmed the lack of efficacy of PEB + BMS strategy compared with DES, although both have shown important heterogeneity, as the employed devices (balloon plus stent) were different in each trial. 26,27 Several reasons can be claimed to explain the lack of efficacy of PEB + (systematic) BMS. First, it is reasonable that the paclitaxel released by PEB can prevent restenosis when vessel injury is confined to BA, but might not be able to negotiate the more powerful intimal response derived from stent implantation. 28 Moreover, the use of a polymer-coating technology in DES 29 is associated with gradual drug release over time, whereas paclitaxelis generally released by PEB in a single “shot.” Paclitaxel bioavailability in the vessel wall also seems to be influenced by the specific PEB technology. 30 Importantly a side-by-side comparison in a porcine model of various PEB demonstrated marked differences in late luminal loss. 30
Limitations First, this trial was prematurely stopped and we are fully aware that our findings should only be interpreted as exploratory. Despite the lack of an independent safety
American Heart Journal Volume 166, Number 5
Liistro et al 925
Figure 3
Figure 4
Kaplan-Meier curves of cumulative incidence at 9 months of IDTLR for PEB + BMS (circles) and for DES (triangle).
Table IV. Clinical, angiographic, and FD-OCT data (n = 24) Clinical Age (y), median (IQR) Male sex, n (%) Current smokers, n (%) Diabetes, n (%) Family history of CAD, n (%) Hypertension, n (%) Dyslipidemia, n (%) Target vessel LAD, n (%) LCx, n (%) RCA, n (%) Stent length (mm), median (IQR) Stent diameter (mm), median (IQR) FD-OCT cross-section analysis Minimal lumen area (mm 2) Minimal stent area (mm 2) Maximal neointimal area (mm 2) Lumen volume (mm 3) Stent volume (mm 3) Neointimal volume (mm 3) Net volume obstruction (%) FD-OCT strut-level analysis Total no. of struts analyzed, n Covered embedded struts per lesion, n (%) Covered protruding struts per lesion, n (%) Uncovered struts per lesion, n (%) Malapposed struts per lesion, n (%)
66 (62-76) 21 (87.5) 10 (41.7) 5 (20.8) 4 (16.7) 13 (54.2) 10 (41.7) 10 (41.7) 6 (25.0) 8 (33.3) 15.0 (13.0-18.0) 3.00 (2.75-3.50) 4.0 (2.3-4.8) 7.0 (5.9-8.5) 3.6 (2.4-4.4) 81 (59.8-101.5) 116.9 (86.4-145.6) 37.9 (34.5-57.8) 35 (26-41) 4304 99 (98-100) 1.5 (0.5-1.8) 0 (0-0) 0 (0-0)
IQR, Interquartile range; CAD, coronary artery disease LAD, left anterior descending; LCx, left circumflex; RCA, right coronary artery.
In this frequency-domain optical coherence tomography image, an example of the typical thick neointimal tissue found at 9 months after PEB + BMS is shown. A single malapposed (but covered) strut is visible, more clearly in the magnified view (upper left panel, dotted line indicates the same strut shadowing in both normal and magnified view).
present in continuing a trial with evidence of a clear inferiority in one of the randomized arms. Second, the high restenosis rate observed in our study might potentially be related to geographical miss. However, stent length was always inferior to the segment treated with PEB. Of note, no evidence of geographical miss was observed in the 24 patients who underwent FDOCT imaging at follow-up. Third, friction between PEB and stenosis surfaces and loss of drug from the balloon are potential drawbacks of PEB technology. However, all lesions were predilated with conventional balloons avoiding extensive contact with the vessel wall during lesion crossing and before deployment. Fourth, the single-center nature of our trial and the absence of a core laboratory for restenosis evaluation must be acknowledged. Last, no FD-OCT follow-up was performed in the DES group. However, financial constraints were present in running a non–industry-funded trial, and the reason for performing FD-OCT was mainly to provide safety data in the PEB + BMS group.
Conclusion monitor or an adjudication committee, we decided to halt the study, after extensive internal discussion, because of a perceived excess of IDTLR in the PEB + BMS group. This has reduced the power of our study and the general applicability of our results. However, ethical issues were
In this study, PEB + BMS was significantly inferior to DES. The development of more sophisticated PEB technologies with different drug carriers capable to enhance drug bioavailability and permanence in the vessel wall will be essential for future studies.
American Heart Journal November 2013
926 Liistro et al
Disclosures None of the Authors has any conflict of interest related to the Manuscript.
17.
References
18.
1. Bangalore S, Kumar S, Fusaro M, et al. Short and long-term outcomes with drug eluting and bare metal coronary stents: a mixed treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation 2012;125:2873-91. 2. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745-54. 3. Speck U, Cremers B, Kelsch B, et al. Do pharmacokinetics explain persistent restenosis inhibition by a single dose of paclitaxel? Circ Cardiovasc Interv 2012;5:392-400. 4. Scheller B, Speck U, Abramjuk C, et al. Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. Circulation 2004;110:810-4. 5. Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drugeluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol 2012;59:1377-82. 6. Ali RM, Degenhardt R, Zambahari R, et al. Paclitaxel-eluting balloon angioplasty and cobalt-chromium stents versus conventional angioplasty and paclitaxel-eluting stents in the treatment of native coronary artery stenoses in patients with diabetes mellitus. EuroIntervention 2011(Suppl K):K83-92. 7. Micari A, Cioppa A, Vadalà G, et al. A new paclitaxel-eluting balloon for angioplasty of femoropopliteal obstructions: acute and midterm results. EuroIntervention 2011(Suppl K):K77-82. 8. Liistro F, Porto I, Grotti S, et al. Drug-eluting balloon angioplasty for carotid in-stent restenosis. J Endovasc Ther 2012;19:729-33. 9. Black AJ, Namay DL, Niederman AL, et al. Tear or dissection after coronary angioplasty. Morphologic correlates of an ischemic complication. Circulation 1989;79:1035-42. 10. Mintz GS, Popma JJ, Pichard AD, et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996;94:35-43. 11. Ruebben ABJ, Weiss N. Drug-eluting balloon analysis. Interv Cardiol (Touch briefings) 2010;4:74-6. 12. Garrone P, Biondi-Zoccai G, Salvetti I, et al. Quantitative coronary angiography in the current era: principles and applications. J Interv Cardiol 2009;22:527-36. 13. Guagliumi G, Costa MA, Sirbu V, et al. Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Circulation 2011;123:274-81. 14. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51. 15. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of instent restenosis: classification and implications for long-term outcome. Circulation 1999;100:1872-8. 16. Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
coronary artery disease: a randomized trial. JAMA 2008;299: 1903-13. Roukoz H, Bavry AA, Sarkees ML, et al. Comprehensive metaanalysis on drug-eluting stents versus bare-metal stents during extended follow-up. Am J Med 2009;122:581.e1-581.e10. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356:1030-9. Pöss J, Jacobshagen C, Ukena C, et al. Hotlines and clinical trial updates presented at the German Cardiac Society Meeting 2010: FAIR-HF, CIPAMI, LIPSIA-NSTEMI, Handheld-BNP, PEPCAD III, remote ischaemic conditioning, CERTIFY, PreSCD-II, German Myocardial Infarction Registry, DiaRegis. Clin Res Cardiol 2010;99:411-7. Fischer D, Scheller B, Schafer A, et al. Paclitaxcel-coated balloon plus bare metal stent vs. sirolimus-eluting stent in de novo lesions: an IVUS study. EuroIntervention 2012;8:450-5. Bourgeois FT, Murthy S, Mandl KD. Outcome reporting among drug trials registered in ClinicalTrials.gov. Ann Intern Med 2010;153: 158-66. Gutiérrez-Chico JL, van Geuns RJ, Koch KT, et al. Paclitaxel-coated balloon in combination with bare metal stent for treatment of de novo coronary lesions: an optical coherence tomography first-in-human randomised trial, balloon first vs. stent first. EuroIntervention 2011;7: 711-22. Poerner TC, Otto S, Janiak F, et al. A prospective randomized study using optical coherence tomography to assess endothelial coverage and neointimal proliferation at 6 months after implantation of a coronary everolimus-eluting stent compared with bare metal stent postdilated with a paclitaxel-eluting balloon (OCTOPUS trial). J Am Coll Cardiol 2012;59:E281. Mieres J, Fernandez-Pereira C, Risau G, et al. One-year outcome of patients with diabetes mellitus after percutaneous coronary intervention with three different revascularization strategies: results from the Diabetic Argentina Registry (DEAR). Cardiovasc Revasc Med 2012;13:265-71. Belkacemi A, Agostoni P, Nathoe HM, et al. First results of the DEBAMI (Drug Eluting Balloon in Acute ST-Segment Elevation Myocardial Infarction) trial: a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drugeluting stent in primary percutaneous coronary intervention with 6month angiographic, intravascular, functional, and clinical outcomes. J Am Coll Cardiol 2012;59:2327-37. Frohlich GM, Lansky AJ, Ko DT, et al. Drug eluting balloons for de novo coronary lesions—a systematic review and meta-analysis. BMC Med 2013;11:123. Zhang T, Sun S, Shen L, et al. Drug-eluting balloons for de novo coronary artery disease: a meta-analysis of angiographic and clinical data. Catheter Cardiovasc Interv 2013;22:1-10. Speck U, Scheller B, Rutsch W, et al. Local drug delivery—the early Berlin experience: single drug administration versus sustained release. EuroIntervention 2011(Suppl K):K17-22. Lansky AJ, Costa RA, Mintz GS, et al. Non–polymer-based paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation 2004;109:1948-54. Radke PW, Joner M, Joost A, et al. Vascular effects of paclitaxel following drug-eluting balloon angioplasty in a porcine coronary model: the importance of excipients. EuroIntervention 2011;7: 730-7.
