Abstract
Background
Several studies investigated the combination of bare metal stents in the main branch and drug-eluting balloons in the side branch in bifurcation lesions, but data on the combination of drug-eluting stents and drug-eluting balloons are scarce. We aim to assess the feasibility of provisional stenting with an everolimus-eluting stent in the main branch and a paclitaxel-eluting balloon in the side branch.
Methods
In this prospective, multi-center study conducted in 5 Australian sites, 35 patients with bifurcation lesions were enrolled. Angiographic and intravascular ultrasound assessments were conducted at 9 months; clinical follow-up was conducted until 12 months.
Results
The primary endpoint, late lumen loss in the side branch measured by quantitative coronary angiography, was 0.10 ± 0.43 mm. No binary restenosis was observed. One patient died; 3 myocardial infarctions (one suspected and two in non-target vessels) and one target lesion revascularization occurred. No probable or definite stent thrombosis was observed.
Conclusion
The combination of an everolimus-eluting stent in the main branch and a paclitaxel-eluting balloon in the side branch appears to be a safe, effective and novel treatment option for bifurcation lesions.
1
Introduction
Bifurcation lesions account for approximately 15% of contemporary percutaneous coronary interventions (PCIs) and are amongst the most technically challenging lesion subsets in PCIs . In the past years, the introduction of drug-eluting stents (DESs) has significantly improved outcomes , and meanwhile, provisional stenting is considered to be the preferable approach for most of the bifurcation lesions . Still, the dilemma of reducing side branch restenosis remains and further investigation into devices that may help to reduce restenosis in bifurcation lesions is warranted.
Drug-eluting balloons (DEBs), being successfully deployed in several indications in coronary and peripheral artery disease , could be a promising treatment modality to reduce side branch restenosis. The updated consensus group recommendations from Kleber et al. as well as a publication of Mathey et al. suggested that provisional stenting with DES in the main branch and DEB in the side branch might be a valuable treatment option which warrants scientific evaluation. We therefore aim to assess the safety and efficacy of provisional stenting with an everolimus-eluting stent in the main branch and a paclitaxel-eluting balloon in the side branch. To the best of our knowledge, only one single center study investigating the combination of DES in the main branch and DEB in the side branch has been published to date . In contrast to BIOLUX-I, this single-center study used the same drug –paclitaxel – for DEB and DES, whereas our study combines a paclitaxel-eluting DEB with a state of the art everolimus-eluting DES.
2
Methods
2.1
Study design and population
BIOLUX-I is a prospective, multi-center, single arm pilot study to assess the feasibility and safety of the Pantera Lux DEB (Biotronik AG, Buelach, Switzerland) for the treatment of symptomatic single de novo bifurcation lesions which are appropriate for provisional stenting technique. Patients were enrolled between January 2011 and August 2012. The trial is registered at www.anzctr.org.au , ID 335843, where the full set of general in- and exclusion criteria is available. Specific angiographic inclusion criteria were: Either a single target lesion or two lesions (target and non-target) located in separate coronary arteries. If a non-target lesion was treated, it had to be treated first. Further, the target lesion had to be a single de novo bifurcation lesion involving a coronary artery with a reference vessel diameter of 2.0 to 4.0 mm in the main branch and side branch with a main branch stenosis of ≥ 50% and < 100%. Lastly, a target vessel thrombolysis in myocardial infarction (TIMI) flow ≥ 2 was required. Specific angiographic exclusion criteria were: Target lesion location in a vessel which has a bypass graft, significant stenosis (> 50%) proximal or distal to the target lesion that might require revascularization or impede runoff, excessively tortuous target vessel (two bends > 90° to reach the target lesion), aorto-ostial or unprotected left main target lesion or target lesion within 5 mm of the origin of the left anterior descending, left circumflex, or right coronary artery, severely calcified target lesion, or evidence of a thrombus, further co-existence of unprotected left main disease (obstruction of > 50%).
Clinical assessments were scheduled at 1, 6, 9 and 12 months. At 9 months additionally angiography and intravascular ultrasound (IVUS) were performed. It was recommended to either use clopidogrel or prasugrel for 6 months and acetylsalicylic acid indefinitely post-procedure. Monitoring included 10% source document verification of key variables. Project and site management as well as data coordination and adjudication was organized by an independent Clinical Research Organization. The Safety Monitoring Committee was composed of physicians from the fields of interventional cardiology who were not directly involved in the conduct of the trial. Angiographic and IVUS assessments were done by an independent core laboratory. Ethics committee approval was obtained for all participating institutions and the clinical trial was conducted in accordance with Good Clinical Practice and ISO14155 as well as local regulations and applicable regulatory requirements. All patients provided written informed consent.
2.2
Procedure
The surface of the Pantera Lux DEB is homogenously coated with a delivery matrix of 3 μg paclitaxel per mm 2 using butyryltri-n-hexyl citrate (BTHC) as an excipient. BTHC incorporates paclitaxel into a micro-crystalline structure to improve drug uptake into the vessel wall . It degrades to citric acid and alcohol. Paclitaxel is a lipophilic anti-proliferative substance that allows a rapid drug absorption by the surrounding tissue. The DEB was available in lengths of 10 to 30 mm with diameters of 2.0 to 4.0 mm.
Pre-dilatation of the main branch with a standard balloon catheter was required. Then, the side branch was treated with Pantera Lux and the main branch with a DES (XienceV/Xience Prime, Abbott Vascular, Santa Clara, CA, USA). Post-dilatation in the main branch was allowed at the investigator’s discretion in order to achieve optimal stent deployment (residual diameter stenosis < 10%). Thereafter, kissing balloon inflation with standard balloons had to be performed. Stenting of the side branch was deemed appropriate in the following cases: prolonged ischemia (attributable to a side branch complication), TIMI Grade flow 0 or 1, dissection in the side branch, > 70% residual stenosis.
2.3
Endpoints and definitions
Lesions were defined according the Medina classification . The primary endpoint was late lumen loss (LLL) of the side branch at 9 months by quantitative coronary angiography (QCA), defined as the difference between the post-index procedure minimal lumen diameter (MLD) and the follow-up MLD. Secondary endpoints were device success, defined as final residual diameter stenosis of < 30% by QCA in the side branch, using the assigned device only, procedural success, defined as final diameter stenosis < 30% by QCA in the side branch and main branch, using the study device, without the occurrence of death, myocardial infarction or repeat target lesion revascularization (TLR) during the hospital stay, and lesion success, defined as final residual diameter stenosis of < 30% by QCA in the side branch without the need for other lesion treatment (like cutting balloon, atherectomy) during the index procedure. Furthermore, a composite of cardiac death, target-vessel myocardial infarction and clinically driven target vessel revascularization (TVR) was assessed at 6, 9 and 12 months, clinically driven TLR at 6, 9 and 12 months and binary angiographic restenosis at 9 months, as measured by QCA. Definitions of cardiac death, myocardial infarction and TLR and stent thrombosis were according to the ARC-Academic Research Consortium guidelines .
2.4
Statistical analysis
The analysis was based on the principle of intention-to-treat (ITT). For this study, all subjects who met the study entry criteria, signed the written informed consent and were enrolled in the trial were counted in the intention-to-treat analysis. The primary analysis consists of descriptive statistics. These are presented as the mean and standard deviation for continuous variables and as frequencies and percentages for discrete variables.
2
Methods
2.1
Study design and population
BIOLUX-I is a prospective, multi-center, single arm pilot study to assess the feasibility and safety of the Pantera Lux DEB (Biotronik AG, Buelach, Switzerland) for the treatment of symptomatic single de novo bifurcation lesions which are appropriate for provisional stenting technique. Patients were enrolled between January 2011 and August 2012. The trial is registered at www.anzctr.org.au , ID 335843, where the full set of general in- and exclusion criteria is available. Specific angiographic inclusion criteria were: Either a single target lesion or two lesions (target and non-target) located in separate coronary arteries. If a non-target lesion was treated, it had to be treated first. Further, the target lesion had to be a single de novo bifurcation lesion involving a coronary artery with a reference vessel diameter of 2.0 to 4.0 mm in the main branch and side branch with a main branch stenosis of ≥ 50% and < 100%. Lastly, a target vessel thrombolysis in myocardial infarction (TIMI) flow ≥ 2 was required. Specific angiographic exclusion criteria were: Target lesion location in a vessel which has a bypass graft, significant stenosis (> 50%) proximal or distal to the target lesion that might require revascularization or impede runoff, excessively tortuous target vessel (two bends > 90° to reach the target lesion), aorto-ostial or unprotected left main target lesion or target lesion within 5 mm of the origin of the left anterior descending, left circumflex, or right coronary artery, severely calcified target lesion, or evidence of a thrombus, further co-existence of unprotected left main disease (obstruction of > 50%).
Clinical assessments were scheduled at 1, 6, 9 and 12 months. At 9 months additionally angiography and intravascular ultrasound (IVUS) were performed. It was recommended to either use clopidogrel or prasugrel for 6 months and acetylsalicylic acid indefinitely post-procedure. Monitoring included 10% source document verification of key variables. Project and site management as well as data coordination and adjudication was organized by an independent Clinical Research Organization. The Safety Monitoring Committee was composed of physicians from the fields of interventional cardiology who were not directly involved in the conduct of the trial. Angiographic and IVUS assessments were done by an independent core laboratory. Ethics committee approval was obtained for all participating institutions and the clinical trial was conducted in accordance with Good Clinical Practice and ISO14155 as well as local regulations and applicable regulatory requirements. All patients provided written informed consent.
2.2
Procedure
The surface of the Pantera Lux DEB is homogenously coated with a delivery matrix of 3 μg paclitaxel per mm 2 using butyryltri-n-hexyl citrate (BTHC) as an excipient. BTHC incorporates paclitaxel into a micro-crystalline structure to improve drug uptake into the vessel wall . It degrades to citric acid and alcohol. Paclitaxel is a lipophilic anti-proliferative substance that allows a rapid drug absorption by the surrounding tissue. The DEB was available in lengths of 10 to 30 mm with diameters of 2.0 to 4.0 mm.
Pre-dilatation of the main branch with a standard balloon catheter was required. Then, the side branch was treated with Pantera Lux and the main branch with a DES (XienceV/Xience Prime, Abbott Vascular, Santa Clara, CA, USA). Post-dilatation in the main branch was allowed at the investigator’s discretion in order to achieve optimal stent deployment (residual diameter stenosis < 10%). Thereafter, kissing balloon inflation with standard balloons had to be performed. Stenting of the side branch was deemed appropriate in the following cases: prolonged ischemia (attributable to a side branch complication), TIMI Grade flow 0 or 1, dissection in the side branch, > 70% residual stenosis.
2.3
Endpoints and definitions
Lesions were defined according the Medina classification . The primary endpoint was late lumen loss (LLL) of the side branch at 9 months by quantitative coronary angiography (QCA), defined as the difference between the post-index procedure minimal lumen diameter (MLD) and the follow-up MLD. Secondary endpoints were device success, defined as final residual diameter stenosis of < 30% by QCA in the side branch, using the assigned device only, procedural success, defined as final diameter stenosis < 30% by QCA in the side branch and main branch, using the study device, without the occurrence of death, myocardial infarction or repeat target lesion revascularization (TLR) during the hospital stay, and lesion success, defined as final residual diameter stenosis of < 30% by QCA in the side branch without the need for other lesion treatment (like cutting balloon, atherectomy) during the index procedure. Furthermore, a composite of cardiac death, target-vessel myocardial infarction and clinically driven target vessel revascularization (TVR) was assessed at 6, 9 and 12 months, clinically driven TLR at 6, 9 and 12 months and binary angiographic restenosis at 9 months, as measured by QCA. Definitions of cardiac death, myocardial infarction and TLR and stent thrombosis were according to the ARC-Academic Research Consortium guidelines .
2.4
Statistical analysis
The analysis was based on the principle of intention-to-treat (ITT). For this study, all subjects who met the study entry criteria, signed the written informed consent and were enrolled in the trial were counted in the intention-to-treat analysis. The primary analysis consists of descriptive statistics. These are presented as the mean and standard deviation for continuous variables and as frequencies and percentages for discrete variables.
3
Results
3.1
Baseline data
In BIOLUX-I, 35 patients were enrolled in 5 Australian centers. The patient flow is displayed in Fig. 1 . Patients treated were predominantly male (82.8%), nearly one quarter had diabetes (22.9%) or previous percutaneous coronary interventions (PCIs) (22.9%). Lesions were mostly located in the left anterior descending artery (82.9%) ( Table 1 ).
| Patient baseline and lesion data | |
|---|---|
| Demographics | |
| Mean age ± SD (years) | 65.9 ± 9.5 |
| Min–Max | 50–82 |
| Male gender | 82.8% (29/35) |
| Medical history | |
| History of smoking | 74.3% (26/35) |
| Diabetes mellitus | 22.9% (8/35) |
| History of hypertension | 68.6% (24/35) |
| History of hyperlipidemia | 82.8% (29/35) |
| Premature CAD in a first degree relative a | 41.2% (14/34) |
| Previous CABG | 2.9% (1/35) |
| Previous PCI | 22.9% (8/35) |
| Stroke or TIA in Last 6 Months | 2.9% (1/35) |
| Mean LVEF (%) | 68 ± 10.4% |
| CCS Class | |
| Class I | 28.6% (10/35) |
| Class II | 42.9% (15/35) |
| Class III | 8.6% (3/35) |
| Class IV | 2.9% (1/35) |
| No angina | 48.6% (6/35) |
| Medina classification b | |
| 1,1,1 | 23.3% (7/30) |
| 1,1,0 | 46.6% (14/30) |
| 1,0,1 | 3.3% (1/30) |
| 1,0,0 | 16.7% (5/30) |
| 0,1,1 | 10.0% (3/30) |
| 0,1,0 | 16.7% (5/30) |
| Bifurcation treated | |
| LAD | 82.8% (29/35) |
| LCX | 8.6% (3/35) |
| RCA | 8.6% (3/35) |
| Previous stenting of MB or SB | 0.0% (0/35) |
| Angulation between distal MB and SB < 70° | 51.4% (18/35) |
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