Author + information
- Received February 24, 2017
- Revision received June 6, 2017
- Accepted June 15, 2017
- Published online September 27, 2017.
- Stefan Verheye, MD, PhDa,∗ (, )
- Mathias Vrolix, MDb,
- Indulis Kumsars, MD, PhDc,
- Andrejs Erglis, MD, PhDc,
- Dace Sondore, MDc,
- Pierfrancesco Agostoni, MD, PhDd,
- Kristoff Cornelis, MDe,
- Luc Janssens, MDf,
- Michael Maeng, MD, PhDg,
- Ton Slagboom, MDh,
- Giovanni Amoroso, MD, PhDh,
- Lisette Okkels Jensen, MD, PhD, DMScii,
- Juan F. Granada, MDj and
- Pieter Stella, MD, PhDk
- aAntwerp Cardiovascular Center, ZNA Middelheim, Antwerp, Belgium
- bDepartment of Cardiology, Ziekenhuis Oost Limburg, Genk, Belgium
- cLatvian Center of Cardiology, Paul Stradins Clinical University Hospital, Riga, Latvia
- dDepartment of Cardiology, St. Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands
- eDepartment of Cardiology, AZ Maria Middelares Ghent, Ghent, Belgium
- fDepartment of Cardiology, Imeldaziekenhuis Bonheiden, Bonheiden, Belgium
- gDepartment of Cardiology, Aarhus University Hospital, Aarhus, Denmark
- hDepartment of Cardiology, OLVG Amsterdam, Amsterdam, the Netherlands
- iDepartment of Cardiology, Odense University Hospital, Odense, Denmark
- jSkirball Center for Innovation, Cardiovascular Research Foundation, Orangeburg, New York
- kDepartment of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
- ↵∗Address for correspondence:
Dr. Stefan Verheye, Antwerp Cardiovascular Center ZNA Middelheim, Interventional Cardiology, Lindendreef 1, Antwerp, Antwerp 2020, Belgium.
Objectives The aim of this first-in-human study was to assess the safety and effectiveness of the Virtue sirolimus-eluting balloon in a cohort of patients with in-stent restenosis (ISR).
Background Angioplasty balloons coated with the cytotoxic drug paclitaxel have been widely used for ISR treatment. The Virtue angioplasty balloon (Caliber Therapeutics, New Hope, Pennsylvania) delivers sirolimus in a nanoencapsulated liquid formulation. This clinical trial is the first to examine a sirolimus-eluting balloon for ISR.
Methods In this prospective, single-arm feasibility study at 9 European centers, 50 ISR patients were treated with the Virtue balloon. Angiographic measurements at 6 months are reported, along with 12-month clinical follow-up.
Results Procedural success in the intention-to-treat population was 100%. The primary safety endpoint was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) assessed at 30 days (0%, n = 50). The primary performance endpoint was in-segment late lumen loss (LLL) at 6 months (0.31 ± 0.52 mm; n = 47). Secondary 6-month endpoints include binary restenosis (19.1%), diameter stenosis (30.3 ± 19.9%), and major adverse cardiac events (MACE) (10.2%, n = 49). In the 36-patient per-protocol population (excluding major protocol violations and previously stented ISR), LLL was 0.12 ± 0.33 mm at 6 months. Clinical outcomes at 1 year for the intention-to-treat group were 12.2% TLF and 14.3% MACE and for the per-protocol population were 2.8% TLF and 2.8% MACE.
Conclusions This first-in-human study showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon, 6-month LLL rates in line with current stent-free ISR treatment options, and clinical outcomes that warrant further evaluation in dedicated randomized studies.
- drug-eluting balloon
- extended release
- in-stent restenosis
- porous angioplasty balloon
- sirolimus nanoparticle
Since the advent of coronary artery stenting, restenosis has taken on a new dimension, insofar as treatment with a second stent results in additional metal layers and polymers that reduce vessel flexibility, promote geometric distortion and lumen deterioration (especially in small vessels), and generally limit the viability of subsequent stenting (1,2). Alternatively, several nonstent treatment options have been tested in randomized clinical trials. The simplest, plain balloon angioplasty, has been associated with failure (major adverse cardiac event [MACE]) rates of 29% to 44% treating coronary in-stent restenosis (ISR) within bare-metal stents (BMS) (3,4). Vascular brachytherapy has exhibited failure rates in the 18% to 28% range and it is not widely available. A more recent development has combined plain balloon angioplasty with the antirestenotic drug paclitaxel in a surface coating, a portion of which is transferred to the arterial wall during angioplasty. Such paclitaxel-coated balloons (PCBs) have proven to be effective (5), with failure rates of 8% to 10% for BMS ISR (6,7) and 17% to 23% for drug-eluting stent (DES) ISR (8–10).
Although PCBs are a feasible treatment option, challenges to this technology remain: 1) the drug paclitaxel is widely considered to be less effective and more toxic than other antirestenotic drugs (i.e., the limus family of sirolimus and its analogs) (11–13); 2) the drug-containing balloon coating has the potential to flake off, causing microemboli when such particulates reach coronary capillary beds fed by the treated arteries; and 3) undefined loss of the coating en route to the target lesion impacts dose accuracy. Attempts to deliver sirolimus via similar methodology as for PCBs have proven unsuccessful due to insufficient tissue uptake and shorter tissue retention of limus drugs compared with paclitaxel (14,15). This pharmacokinetic property of the limus family has called into question the feasibility of mimicking PCBs with limus-coated balloons. Recently, however, the technique of packaging labile drug molecules within particles has been applied to this class of drugs (e.g., sirolimus has been nanoencapsulated within a phospholipid bilayer and delivered to porcine coronary arteries from a balloon surface coating) (16). Indeed, further attempts to coat balloons with sirolimus have recently been published (17). Nevertheless, both nanoparticle-containing and conventional balloon coatings still face the challenges of releasing downstream particulates from the balloon coating, and loss of coating en route to the lesion.
The Virtue sirolimus-eluting angioplasty balloon (Caliber Therapeutics, New Hope, Pennsylvania) has combined the promising approach of encapsulation of sirolimus in submicron particles with angioplasty without a balloon coating (Figure 1). Instead, a liquid formulation is delivered through precise micropores in the balloon, concurrently with angioplasty (18). In extensive preclinical testing sirolimus tissue levels have been shown to persist above or at the therapeutic dose of 1 ng/mg through 28 days post-procedure (18).
The SABRE (Sirolimus Angioplasty Balloon for Coronary In-Stent Restenosis) trial was a prospective, single-arm, feasibility study involving 9 European centers to evaluate the safety and effectiveness of the Virtue balloon for coronary ISR, and powered to demonstrate superiority over (historically documented) plain balloon angioplasty treatment. Patients were evaluated clinically at 30 days, 6 months, and 1 year. Quantitative coronary angiography (QCA) was performed at the 6-month follow-up visit and analyzed by the independent Cardiovascular Research Foundation core lab (New York, New York). The SABRE trial followed the provisions of the Declaration of Helsinki, informed consent was given by all patients, approvals were obtained from local ethics committees of participating centers and Competent Authorities of participating countries, and operators were trained in the use of the Virtue balloon. Site management, monitoring, and data management were performed by a contract research organization (Genae Associates, Antwerp, Belgium) and clinical data were entered in an electronic database, e-capture.net v.9 (Genae Associates) by trained site representatives. Adverse events were adjudicated by a Clinical Events Committee and the trial was overseen by a Data Safety Monitoring Board. Adjudicated data were compiled and analyzed by the Cardiovascular Research Foundation and delivered to Caliber Therapeutics (New Hope, Pennsylvania), where additional review and statistical analyses were conducted.
From November 14, 2013, to January 15, 2015, 50 patients suffering from ISR were enrolled by 14 investigators at 9 clinical sites in 4 countries. Key inclusion criteria included patients >18 years of age, eligible for coronary revascularization with documented evidence of ischemia, and without unstable angina for at least 72 h. Angiographic entry criteria included reference vessel diameter (RVD) by visual estimate of 2.5 to 3.5 mm, target lesion in a native coronary artery with previous BMS or DES, successful pre-dilatation with residual stenosis ≤40%, target lesion length ≤21 mm, target lesion distance ≥5 mm from left anterior descending artery or left circumflex artery or right coronary artery ostium or side branch (>2 mm), and no other lesions within the target vessel. Key exclusion criteria were enrollment in another trial; plans for surgical intervention within 7 months of enrollment; recent (≤72 h) unstable coronary syndromes; stroke within 6 months prior to enrollment; left ventricular ejection fraction <30%; >1 critical lesion (requiring treatment) in a nontarget vessel; target lesions extending >2 mm outside of stent; total occlusion; and thrombus.
Percutaneous transluminal coronary angioplasty catheters (140 cm, rapid exchange) were fitted with standard semicompliant angioplasty balloons (diameter 2.5, 2.75, 3.0, 3.25, and 3.5 mm; length 15, 20, and 25 mm) that were laser drilled with holes of uniform pattern and density. Sirolimus was encapsulated, with biodegradable polyester-based polymers, in submicron particles that are stable in aqueous suspension, lyophilized in the presence of lyoprotectants, and radiation sterilized. The sirolimus formulation was reconstituted with sterile water containing 20% contrast, and loaded via a stopcock port (with an extension tube to provide the required dose volume), displacing ambient air in the balloon and catheter. An indeflator containing normal saline was connected to the stopcock such that saline from the indeflator pushed formulation from the extension tube, through the catheter, and through the balloon pores. The extension tube length was customized according to balloon size, including a pre-determined added volume of formulation to eliminate dilution with saline from the indeflator. Thus, a precise volume of formulation was delivered to the vessel wall at standard angioplasty pressure (10 to 14 atm) for 30 to 60 s.
Percutaneous access (radial or femoral) complied with standard procedure at each center; heparin or other anticoagulant therapy was administered to maintain activated clotting time >250 s; acetylsalicylic acid (75 to 325 mg/day indefinitely) along with an additional antiplatelet therapy (e.g., clopidogrel 300 to 600 mg loading dose and 75 mg/day maintenance) was begun pre-procedure and continued for at least 3 months. Intracoronary nitroglycerin (50 to 200 μg) was administered prior to all angiography. Lesions were pre-dilatated with plain, scoring, or cutting angioplasty balloons, after which angiography was performed. If a good angiographic result was obtained (≤40% diameter stenosis), the Virtue balloon was deployed so as to deliver 12 μg sirolimus per square millimeter of balloon surface. QCA measurements were obtained after Virtue deployment. Post-dilatation or “bailout” stenting in response to a suboptimal angiographic result (blocked flow or high percent residual stenosis) was left to the operator’s discretion.
Follow-up and study endpoints
Clinical assessment was performed at 30 days, 6 months (QCA), and 1 year after the index procedure; 2- and 3-year clinical follow-up will also take place. Follow-ups were done by telephone for all but the 6-month visit and clinical events. The primary safety endpoint was target lesion failure (TLF) at 30 days, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization (TLR). The primary performance endpoint was 6-month in-segment late lumen loss (LLL) by QCA, defined as the difference between minimal lumen diameter immediately post-procedure and at follow-up in the segment defined by the lesion or treatment zone ±5 mm.
Secondary endpoints include binary restenosis at 6 months follow-up (≥50% diameter stenosis by QCA); percent MACE (death, target vessel myocardial infarction, bypass surgery, or TLR), per Clinical Events Committee adjudication, in hospital, at 30 days, 6 months, 1 year, 2 years, and 3 years; device success (advancement, angioplasty concurrent with dose delivery, and retrieval); and procedural success (device success without MACE during index hospitalization).
QCA analysis was performed by the Cardiovascular Research Foundation core lab using Medis QAngio software (version 7.2.34, Leiden, the Netherlands). Angiograms from each patient were analyzed at baseline, after pre-dilatation, post-treatment, and at 6 months follow-up. RVD is calculated (internormal) from proximal and distal measurements outside of the lesion or stented zones. Percent diameter stenosis is calculated as: (1 − [minimal lumen diameter / RVD]) × 100.
The primary performance endpoint (in-segment LLL by QCA at 6 months) was chosen to be compared with a performance goal determined from previous studies (7,8,19) that used plain balloon angioplasty for ISR treatment, with a weighted average in-segment LLL value of 0.86 mm. Using a superiority design (null hypothesis of Virtue not different from plain balloon angioplasty, with a 90% power and an alpha value of 0.025 [1-sided]) and a conservative target LLL for Virtue of 0.43 ± 0.61 (based on the PCB arm of the PEPCAD-DES (PEPCAD DES-Treatment of DES-In-Stent Restenosis With SeQuent® Please Paclitaxel Eluting PTCA Catheter) trial) (8), 24 patients were required to demonstrate superiority of Virtue over plain balloon angioplasty. The sample size was doubled to 50 patients to allow for losses in angiographic follow-up and to provide additional confidence around the unpowered primary safety endpoint (TLF at 30 days post-procedure).
Continuous data (mean ± SD) and categorical data (values and percentages) for all patients were compiled at the Cardiovascular Research Foundation Clinical Trials Center (New York, New York), except for stent diameter, which was collected by Caliber Therapeutics from case logs. LLL comparisons with the performance goal were performed at the Cardiovascular Research Foundation (using a Wilcoxon signed rank test). Statistical interactions among the 9 centers and 4 countries represented in the SABRE trial were analyzed for primary endpoints, using an analysis of variance. At Caliber Therapeutics, for continuous variables, the per-protocol (PP) and excluded subsets were compared by t test (applying Welch’s correction for unequal variances as needed) or Mann-Whitney U test (for non-Gaussian distributions). Frequency data were analyzed using chi-square or Fisher’s exact test, depending on minimal attribute count; p values <0.05 were considered to be statistically significant.
During the study, 51 patients at 9 centers were enrolled with informed consent; 1 patient failed to meet inclusion criteria on the day of the procedure and did not receive Virtue treatment, leaving 50 in the intention-to-treat (ITT) group. Furthermore, 1 patient withdrew informed consent, and 2 others declined angiography prior to the 6-month follow-up visit (Figure 2). Baseline angiographic analysis by the core lab revealed a number of potential protocol inclusion violations (e.g., close proximity to ostium or major side branch, excessive lesion length or number, geographic miss of lesion or stent); a team of 3 independent physicians evaluated those findings, and additional analysis by the core lab identified 8 major ostial or side branch violations and 3 major legion length or number violations. Another 3 patients with re-restenosis (previously stented ISR), were also removed from the PP population because re-restenosis is a confounding factor due to multiple stent layers or drug treatments that could affect procedures and performance in a clinical trial. Thus, 36 patients in the PP population were analyzed separately from the ITT group (Figure 2).
Baseline characteristics of all 50 patients were comparable to other percutaneous coronary intervention trials except for the longer average time since the previous percutaneous coronary intervention (3.9 ± 4.7 years) compared with prior ISR studies (6,9) (Table 1). No significant differences in baseline characteristics were observed between the PP and excluded groups (Table 1). Procedural success was achieved in all patients. Angiographic and procedural characteristics were unremarkable (Table 2). On average, the Virtue balloon was expanded for about 40 s at 13.9 atm, not unlike typical percutaneous angioplasty procedures. Three “bailout” stents were placed due to dissections (grades A, B, and C) during the procedure, none of which was within the target lesion or stent.
No TLFs were reported through the 30-day follow-up (primary safety endpoint) for the entire 50 patient study population. Among the 49 ITT patients at the 6-month follow-up, 1 underwent coronary bypass surgery and 4 received TLR (Table 3), for a TLF rate of 8.2% and a MACE rate of 10.2%; both TLF and MACE rates were 2.8% for the PP group.
Angiographic follow-up at 6 months was performed in 47 patients. Analysis of the ITT group revealed a mean 30.3 ± 19.9% diameter stenosis, with 12.7 ± 20.6% change in diameter stenosis since the index procedure. In-segment LLL, the primary performance endpoint for the SABRE trial, was 0.31 ± 0.52 mm (Table 4), which met the established criterion for superiority to historical plain balloon angioplasty values (p < 0.0001). The secondary performance endpoint for the trial, binary restenosis, was 19.1% at 6 months. Minimum lumen diameters for the ITT group are plotted at baseline, post–index procedure, and at 6 months follow-up (Figure 3). Key angiographic values for the PP group were LLL of 0.12 ± 0.33 mm and 2.8% binary restenosis.
At 1 year, clinical follow-up was obtained for the 49-patient ITT population. Two additional TLRs were reported for an overall TLF rate of 12.2%, and the 1-year MACE rate was 14.3%. For the PP subset, TLF and MACE rates both were 2.8% (Table 3) at 1-year follow-up. No statistically significant differences among centers or countries in the SABRE trial were observed for primary outcomes in the ITT group.
This prospective, multicenter study aimed to demonstrate the safety and feasibility of a sirolimus angioplasty balloon for treatment of coronary ISR. The primary safety endpoint for the SABRE trial, TLF at 30 days (none), was successful, and composite safety endpoints at 12-month clinical follow-up (TLF 12.2% and MACE 14.3%) and angiographic performance (LLL 0.31 ± 0.52 mm at 6 months) are within the ranges established by recent randomized ISR trials (4). Our primary conclusion is thus that the use of a microporous balloon to deliver sirolimus nanoparticles to the vessel wall was both feasible and safe. This may represent a new approach to treatment of ISR.
Treatment of coronary ISR has been addressed with plain balloon angioplasty, brachytherapy, cutting balloons, atherectomy, repeat stenting with BMS and DES, and most recently with PCBs. DES became the current standard of care insofar as the metal scaffold helped to maintain lumen diameter while controlling repeat neointimal hyperplasia with paclitaxel or a limus drug, with improved outcomes compared with prior therapies. A limitation of this approach is the addition of concentric layers of metal that progressively reduces vessel flexibility and lumen diameter, whereas stimulating neointimal hyperplasia and requiring long-term use of dual antiplatelet therapy. The recent advent of PCBs has provided a viable stent-free alternative to DES, with long-term results that have been shown to be better than (7), similar to (6,10), or different from (9) various DES. The superiority of limus-eluting over paclitaxel-eluting stents (12,13) suggests that a stent-free sirolimus angioplasty balloon could have efficacy advantages over current PCBs (11).
BMS ISR is easier to treat than DES ISR (3). Combinations of antirestenotic drugs (20) and that the underlying condition is more likely to be neoatherosclerosis for DES than for BMS ISR (3) could be factors influencing outcome. For instance, in the RIBS V (Restenosis Intra-stent of Bare Metal Stents: Paclitaxel-eluting Balloon vs. Everolimus-eluting Stent) trial, 1-year TLR rates for BMS ISR were 6% for PCB, compared with the SABRE trial TLR rate of 3% (not shown), whereas for DES ISR TLR rates from the RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloon vs Everolimus-Eluting Stent) trial were 13% for PCBs, compared with 29% from the SABRE trial. This higher TLR rate for Virtue-treated DES ISR may be due to the small sample size (n = 17) of this subset, along with the following differences among patient populations: the time to restenosis in the RIBS IV and V trials was 1.5 years and 1.1 years, respectively, compared with 3.9 years since the previous percutaneous coronary intervention in the SABRE trial; in the RIBS IV trial 25% of patients displayed PES restenosis compared with 12% in the SABRE trial; and diffuse lesions (Mehran II to IV) made up 37% of lesions in the RIBS IV trial compared with 66% in the SABRE trial. Overall, the patient population in the SABRE trial was a relatively difficult one, which reinforces the low TLF rate (3.1%) in the BMS ISR subgroup (n = 32).
Performance data from PCB trials for ISR also serve as a relevant comparison to the SABRE trial. Six-month LLL in the PACCOCATH I and II (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons) trials was 0.11 ± 0.44 mm (7). As in the SABRE trial, the PACCOCATH trials treated both BMS and DES ISR patients. A similar result (LLL 0.18 ± 0.45 mm) was seen in a large retrospective trial (19), using heterologous treatment of limus ISR with PCB. On the other hand, in the PEPCAD-DES trial, PCB treatment of either paclitaxel- or limus-eluting stent ISR gave equivalent results (LLL 0.46 ± 0.50 mm and 0.41 ± 0.65 mm, respectively) (8). LLL in the SABRE trial ITT group, at 0.31 ± 0.52 mm, and PP subset (0.12 ± 0.33 mm) were comparable to these and to more recent trials: 0.14 ± 0.50 mm for BMS ISR in the RIBS V trial (6); and 0.30 ± 0.60 mm for DES ISR in the RIBS IV trial (9). Treatment of ISR lesions with current-generation DES (primarily containing the sirolimus analog, everolimus) is commonplace and, despite the complication of comparing stented with stent-free treatments, is a relevant metric. Nine-month LLL for BMS ISR treated with DES was 0.04 ± 0.50 mm in the RIBS V trial (6), and 0.18 ± 0.60 mm for DES-treated DES ISR in the RIBS IV trial (9), both numerically but not statistically lower than the corresponding PCB values.
Analysis of patients excluded from the PP group revealed a significantly different angiographic profile at the 6-month follow-up compared with included patients (Table 4). In particular, minimum lumen diameter for the excluded group (1.09 ± 0.61 mm) was significantly lower than that of the PP subset. Given the criteria for exclusion (ostial, longer than treatment device, and extrastent lesions; and multiple stent layers—all risk factors for neointimal growth) (2,21), this is not unexpected. Such procedural characteristics are typically excluded from ISR clinical trials due to recalcitrance or variable response to treatment, making it difficult to interpret in a clinical trial setting. The PP group represents a patient population that would be anticipated in future assessment of the Virtue balloon in randomized clinical trials.
Lesion preparation has been widely recommended prior to drug eluting balloon deployment (1). In the SABRE trial, each lesion was pre-dilatated according to the investigators’ preferences, using semicompliant, noncompliant, cutting, or scoring balloons, with the intention of providing a receptive microenvironment for local uptake and retention of the sirolimus liquid formulation during angioplasty. However, most Virtue deployments in a porcine coronary artery model were performed without pre-dilatation. Although pre-dilatation might enhance tissue uptake of the Virtue formulation, sirolimus levels seen preclinically confirm that pre-dilatation is not a necessary condition for drug uptake (18). Nevertheless, it cannot be ruled out that variability in lesion preparation might have promoted variability in formulation uptake and therapeutic outcome.
Finally, further analysis of the PP subset reveals an interesting relationship between resulting BMS and DES ISR subgroups for LLL: 0.10 ± 0.31 mm for BMS ISR (n = 26) and 0.20 ± 0.38 mm for DES ISR (n = 10), not statistically different (p = 0.42).
Limitations of the SABRE trial include the small sample size and single-arm design that would limit applying conclusions to broad patient populations, although no significant differences for primary outcomes were found among centers or countries within the trial. Additionally, a significant portion (28%) of patients in the SABRE trial was excluded from the PP subset, further limiting the sample size for that analysis.
In summary, the results of the SABRE trial establish a reasonably safe and effective alternative treatment, for ISR lesions: to 1) balloon coatings with theoretical potential for downstream embolization; 2) use of the mitotic inhibitor paclitaxel (22); and 3) implanting additional layers of metal in diseased arteries, with concomitant long-term dual antiplatelet therapy and limited future treatment options. The acceptable QCA and composite clinical outcomes for the Virtue angioplasty balloon in a challenging patient population warrant further evaluation in appropriately powered clinical trials.
WHAT IS KNOWN? Treatment of BMS ISR and, increasingly, DES ISR is clinically challenging. Recent treatment recommendations include both paclitaxel coated balloons and current generation limus-eluting stents, in addition to plain balloon angioplasty.
WHAT IS NEW? A novel porous sirolimus-eluting angioplasty balloon has been shown to be safe and effective in a prospective multicenter 50-patient clinical trial, providing a potential alternative to paclitaxel treatment in patients where additional stent layers or associated long-term dual antiplatelet therapy are not desired.
WHAT IS NEXT? The results of the SABRE trial warrant further evaluation of the Virtue sirolimus-eluting angioplasty balloon.
The SABRE trial was sponsored by Caliber Therapeutics, Inc. (New Hope, Pennsylvania). Dr. Maeng has received research grant support from Boston Scientific, Biosensors, and Volcano. Dr. Slagboom is a consultant with Biotronik. 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
- intention to treat
- late lumen loss
- major adverse cardiac events
- paclitaxel-coated balloon
- per protocol
- quantitative coronary angiography
- reference vessel diameter
- target lesion failure
- target lesion revascularization
- Received February 24, 2017.
- Revision received June 6, 2017.
- Accepted June 15, 2017.
- 2017 American College of Cardiology Foundation
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