2.1

Study design and organization

The BioFreedom USA trial was designed as a prospective multicenter study aimed at investigating the safety and efficacy of the polymer-free BF Biolimus A9-coated stent in stable patients undergoing PCI with a short duration of DAPT (3 months). The trial was sponsored by Biosensors Research USA Inc., and the investigational device exemption for this feasibility study was granted by the US Food and Drug Administration. Data coordination, storage, management, and statistical analysis were performed by an independent data coordinator center (MedStar Cardiovascular Research Network, Washington, DC).

2.2

Study population

BioFreedom USA was an open-label, single-arm study of patients who required stenting of de novo lesions. The main inclusion criteria were ≥ 18 years in age and clinical evidence of ischemic heart disease due to native coronary artery stenosis. Subjects had to be acceptable candidates for PCI, stenting, and emergent coronary artery bypass grafting. Additionally, they had to meet a set of angiographic criteria, including de novo target lesions, and one or two lesions in different vessels that had not been previously treated with any interventional procedure. Lesions had to have a stenosis > 70% by visual estimate, and target lesions had to be < 27 mm in length with the intent to be covered by a single study stent. Reference vessel diameters had to be between ≥ 2.25 mm and ≤ 4.0 mm. Patients were asked to agree to a 9-month angiographic re-evaluation. Exclusion criteria included hypersensitivity to or intolerance of aspirin, heparin, clopidogrel, or contrast agents; inability to take clopidogrel for 3 months or co-morbidities that would prevent clopidogrel cessation at 3 months; history of stroke within 6 months; acute peptic ulcer or upper gastrointestinal bleeding within 6 months; and history of active bleeding diathesis or coagulopathy.

Primary data collection was performed at each clinical site following standard procedure, including physical completion of individual case report forms and on-site monitoring. Clinical follow-up was conducted at 9 months, with telephone or office visits at the 1-, 3-, 4-, 6-, and 12-month follow-up. All primary or secondary end point-related events were adjudicated by an independent clinical events committee. The study is ongoing, with clinical follow-up planned out to 5 years.

2.3

Study device and anti-proliferative drug BA9

The BioFreedom drug-eluting coronary stent delivery system (Biosensors International, Singapore) comprises three key components, including (1) a 316 L stainless steel platform that has been modified with a proprietary surface treatment using a micro-abrasion process resulting in a selectively micro-structured, abluminal surface, (2) BA9 drug coating, and (3) delivery system. The micro-structured surface contains the anti-proliferative drug, BA9, on the abluminal surface of the stent without the use of a polymer or binder.

BA9 is a highly lipophilic, semi-synthetic sirolimus analogue, allowing sustained high tissue concentration for neointimal suppression. Release kinetic studies have demonstrated that 98% of the drug is released to the vessel wall within 28 days . Due to high lipophilicity that is about 10 times as higher than sirolimus, BA9 can transfer to the vessel wall and treat the lesion site over an extended period of time . The study stent was available in diameters ranging from 2.25 mm to 4.0 mm, and stent lengths of 8, 14, 18, 24, and 28 mm.

2.4

Study procedures

Only one stent was allowed per target lesion with the exception of bailout situations. Predilatation was required prior to the implementation of the BF polymer-free BA9-coated stent. A subgroup of patients was assigned to intravascular ultrasound (IVUS) interrogation at baseline and follow-up. Post-procedure cardiac enzymes were collected at 6–8 h, 12–16 h, and 20–24 h, with an electrocardiogram being performed within 24 h post-procedure. Patients were prescribed DAPT prior to discharge with the requirement of cessation of clopidogrel at 3 months and continuation of single antiplatelet therapy (aspirin) indefinitely.

2.5

Study end points

The primary effectiveness end point of this study was in-stent late lumen loss (LLL) at 9 months as compared to a historical control . The primary safety end point was the occurrence of MACE, defined as the composite of cardiac death, myocardial infarction, target lesion revascularization and academic research consortium (ARC) definite stent thrombosis within 9 months following the implantation. Of note, the study was powered for the primary effectiveness end point.

Secondary end points included all-cause mortality and target vessel revascularization (TVR) at 9 months and MACE, all-cause mortality, and TVR at 12 months.

There was an IVUS substudy to assess volumetric lesion parameters, including neointimal hyperplasia volume, neointimal volume index, and in-stent neointimal volume obstruction at 9 months.

2.6

Angiographic and IVUS analysis

All coronary angiographic images were collected pre-procedure, post-procedure, and at follow-up. Nitroglycerin and balloon predilatation were recommended per the protocol with a minimum requirement of two orthogonal views that show the target lesion(s) without foreshortening or vessel overlap using a 6 Fr or larger guide catheter. All coronary angiograms from the index procedure and post-procedure IVUS assessments, as applicable, were quantitatively analyzed at an independent imaging core lab (MedStar Cardiovascular Research Network Invasive Imaging Core Lab, Washington, DC). The quantitative analyses were performed by experienced operators blinded to procedural data and individual clinical outcomes. Analyses were performed with validated QCA software (Medis QAngio) and IVUS software for transverse volumetric analysis (QIvus). LLL was determined on a per-lesion basis as the mean difference between the in-stent minimum lumen diameter at 9-month follow-up minus the corresponding in-stent minimum lumen diameter post-index procedure. Binary restenosis was defined as the rate of stenosis > 50% at angiographic follow-up on a per-lesion basis. QCA measurements were reported as “in-stent” and as “in-lesion,” meaning the stent plus a 5 mm margin on both ends. Neointimal hyperplasia volume was defined as the stent volume minus the lumen volume, and compared between 9 months and post-procedural assessments.

2.7

Statistical analysis and sample size justification

This single-arm study was designed for comparison of the primary end point LLL with a historical control. Escolar et al. published a cumulative 9-month in-stent late loss for the Taxus Express stent of 0.41 ± 0.56 mm, derived from a total of 216 patients from the Taxus IV, V, and VI trials . With the assumption of a 0.21 mm mean in-stent late loss of the BF DCS at 9 months, a minimum of 64 evaluable lesion pairs were needed to assess the superiority over the Taxus stent with a power of 80%. The site investigators’ goal was to enroll up to 100 patients to ensure this sample size requirement would be met.

The null and alternative hypotheses for this study are listed below:

• 1.
  

  Ho: BCS ≥ μ Taxus Express

  
  
• 2.
  

  Ha: BCS < μ Taxus Express

The rejection of the null hypothesis would indicate that the BF DCS is non-inferior to the first-generation DES (Taxus) with regard to efficacy as measured by LLL at 9 months. The estimated sample size for this trial is based on a 1-sample t -test at an alpha (2-sided) of 0.05 significance level with an 80% power to reject the null hypothesis of superiority of BF BA9-coated coronary stent over the historical control Taxus Express stent.

Categorical variables are expressed as numbers and percentages of the total. Continuous variables are expressed as mean ± SD.

2.1

Study design and organization

The BioFreedom USA trial was designed as a prospective multicenter study aimed at investigating the safety and efficacy of the polymer-free BF Biolimus A9-coated stent in stable patients undergoing PCI with a short duration of DAPT (3 months). The trial was sponsored by Biosensors Research USA Inc., and the investigational device exemption for this feasibility study was granted by the US Food and Drug Administration. Data coordination, storage, management, and statistical analysis were performed by an independent data coordinator center (MedStar Cardiovascular Research Network, Washington, DC).

2.2

Study population

BioFreedom USA was an open-label, single-arm study of patients who required stenting of de novo lesions. The main inclusion criteria were ≥ 18 years in age and clinical evidence of ischemic heart disease due to native coronary artery stenosis. Subjects had to be acceptable candidates for PCI, stenting, and emergent coronary artery bypass grafting. Additionally, they had to meet a set of angiographic criteria, including de novo target lesions, and one or two lesions in different vessels that had not been previously treated with any interventional procedure. Lesions had to have a stenosis > 70% by visual estimate, and target lesions had to be < 27 mm in length with the intent to be covered by a single study stent. Reference vessel diameters had to be between ≥ 2.25 mm and ≤ 4.0 mm. Patients were asked to agree to a 9-month angiographic re-evaluation. Exclusion criteria included hypersensitivity to or intolerance of aspirin, heparin, clopidogrel, or contrast agents; inability to take clopidogrel for 3 months or co-morbidities that would prevent clopidogrel cessation at 3 months; history of stroke within 6 months; acute peptic ulcer or upper gastrointestinal bleeding within 6 months; and history of active bleeding diathesis or coagulopathy.

Primary data collection was performed at each clinical site following standard procedure, including physical completion of individual case report forms and on-site monitoring. Clinical follow-up was conducted at 9 months, with telephone or office visits at the 1-, 3-, 4-, 6-, and 12-month follow-up. All primary or secondary end point-related events were adjudicated by an independent clinical events committee. The study is ongoing, with clinical follow-up planned out to 5 years.

2.3

Study device and anti-proliferative drug BA9

The BioFreedom drug-eluting coronary stent delivery system (Biosensors International, Singapore) comprises three key components, including (1) a 316 L stainless steel platform that has been modified with a proprietary surface treatment using a micro-abrasion process resulting in a selectively micro-structured, abluminal surface, (2) BA9 drug coating, and (3) delivery system. The micro-structured surface contains the anti-proliferative drug, BA9, on the abluminal surface of the stent without the use of a polymer or binder.

BA9 is a highly lipophilic, semi-synthetic sirolimus analogue, allowing sustained high tissue concentration for neointimal suppression. Release kinetic studies have demonstrated that 98% of the drug is released to the vessel wall within 28 days . Due to high lipophilicity that is about 10 times as higher than sirolimus, BA9 can transfer to the vessel wall and treat the lesion site over an extended period of time . The study stent was available in diameters ranging from 2.25 mm to 4.0 mm, and stent lengths of 8, 14, 18, 24, and 28 mm.

2.4

Study procedures

Only one stent was allowed per target lesion with the exception of bailout situations. Predilatation was required prior to the implementation of the BF polymer-free BA9-coated stent. A subgroup of patients was assigned to intravascular ultrasound (IVUS) interrogation at baseline and follow-up. Post-procedure cardiac enzymes were collected at 6–8 h, 12–16 h, and 20–24 h, with an electrocardiogram being performed within 24 h post-procedure. Patients were prescribed DAPT prior to discharge with the requirement of cessation of clopidogrel at 3 months and continuation of single antiplatelet therapy (aspirin) indefinitely.

2.5

Study end points

The primary effectiveness end point of this study was in-stent late lumen loss (LLL) at 9 months as compared to a historical control . The primary safety end point was the occurrence of MACE, defined as the composite of cardiac death, myocardial infarction, target lesion revascularization and academic research consortium (ARC) definite stent thrombosis within 9 months following the implantation. Of note, the study was powered for the primary effectiveness end point.

Secondary end points included all-cause mortality and target vessel revascularization (TVR) at 9 months and MACE, all-cause mortality, and TVR at 12 months.

There was an IVUS substudy to assess volumetric lesion parameters, including neointimal hyperplasia volume, neointimal volume index, and in-stent neointimal volume obstruction at 9 months.

2.6

Angiographic and IVUS analysis

All coronary angiographic images were collected pre-procedure, post-procedure, and at follow-up. Nitroglycerin and balloon predilatation were recommended per the protocol with a minimum requirement of two orthogonal views that show the target lesion(s) without foreshortening or vessel overlap using a 6 Fr or larger guide catheter. All coronary angiograms from the index procedure and post-procedure IVUS assessments, as applicable, were quantitatively analyzed at an independent imaging core lab (MedStar Cardiovascular Research Network Invasive Imaging Core Lab, Washington, DC). The quantitative analyses were performed by experienced operators blinded to procedural data and individual clinical outcomes. Analyses were performed with validated QCA software (Medis QAngio) and IVUS software for transverse volumetric analysis (QIvus). LLL was determined on a per-lesion basis as the mean difference between the in-stent minimum lumen diameter at 9-month follow-up minus the corresponding in-stent minimum lumen diameter post-index procedure. Binary restenosis was defined as the rate of stenosis > 50% at angiographic follow-up on a per-lesion basis. QCA measurements were reported as “in-stent” and as “in-lesion,” meaning the stent plus a 5 mm margin on both ends. Neointimal hyperplasia volume was defined as the stent volume minus the lumen volume, and compared between 9 months and post-procedural assessments.

2.7

Statistical analysis and sample size justification

This single-arm study was designed for comparison of the primary end point LLL with a historical control. Escolar et al. published a cumulative 9-month in-stent late loss for the Taxus Express stent of 0.41 ± 0.56 mm, derived from a total of 216 patients from the Taxus IV, V, and VI trials . With the assumption of a 0.21 mm mean in-stent late loss of the BF DCS at 9 months, a minimum of 64 evaluable lesion pairs were needed to assess the superiority over the Taxus stent with a power of 80%. The site investigators’ goal was to enroll up to 100 patients to ensure this sample size requirement would be met.

The null and alternative hypotheses for this study are listed below:

• 1.
  

  Ho: BCS ≥ μ Taxus Express

  
  
• 2.
  

  Ha: BCS < μ Taxus Express

The rejection of the null hypothesis would indicate that the BF DCS is non-inferior to the first-generation DES (Taxus) with regard to efficacy as measured by LLL at 9 months. The estimated sample size for this trial is based on a 1-sample t -test at an alpha (2-sided) of 0.05 significance level with an 80% power to reject the null hypothesis of superiority of BF BA9-coated coronary stent over the historical control Taxus Express stent.

Categorical variables are expressed as numbers and percentages of the total. Continuous variables are expressed as mean ± SD.