2.1

Study population, devices, randomization and intervention protocol

The P olymer Degrading-S i ro l imus Eluting-C o ronary Stent T rial (PILOT) was a prospective, multi-center pilot trial, enrolling a total of 20 patients, who were randomly assigned to treatment with either BP-SES or EES. Eligible patients (age, ≥ 18 years and < 80 years) had angina pectoris and/or objective signs of ischemia, in the presence of a ≥ 50% diameter stenosis de novo native coronary artery lesion. Key exclusion criteria included patients with cardiogenic shock, left ventricular function < 40%, presence of ≥ 2 target vessels or known hypersensitivity or allergy or contra-indication to contrast agents, aspirin, heparin, ticlopidine and clopidogrel. Lesions with excessive target lesion tortuosity, chronic total occlusion (older than 3 months), and ostial main vessel location were also excluded. The study complied with the declaration of Helsinki, was approved by all institutional ethics committees. All patients provided written informed consent for participation in the trial.

Allocation to treatment was made by means of sealed, opaque envelopes containing a computer-generated sequence. Randomization was performed after the decision to proceed with percutaneous coronary intervention and after crossing of the lesion with a guidewire. Patients who met all of the inclusion criteria and none of the exclusion criteria were randomised in the order that they qualified. Patients were assigned to receive BP-SES (ITRIX, AMG International GmbH, RAesfeld, Borken, Germany) or EES (Xience, Abbott Vascular, Santa Rosa, CA, USA). The ITRIX biodegradable polymer sirolimus-eluting stent is a laser-cut slotted tube stent with a multi-cellular architecture. After electropolishing and carbonizing, the stent is coated with a thin layer (5 μm) of biodegradable polymer, Poly dl -lactic-co-glycolic acid (PLGA). PLGA 50/50 is synthesized from polylactide and polyglycolide in 1:1 rate. The degradation process of this polymer is completed within 8 weeks and its degradation products (lactic and glycolic acid) are completely assimilated by human cell metabolism. The comparator EES is coated with everolimus at a dose of 100 μg/cm of stent surface and a non-biodegradable fluoropolymer, designed to release 80% of the everolimus in the first 30 days after deployment.

2.2

Data management, end points, and definitions

All patients had quantitative coronary angiograms (QCA) at baseline and immediately after PCI. Digital coronary angiograms were analyzed offline at the core laboratory (ISAR Center, Munich, Germany) with a validated automated edge detection system (QAngio XA v7.1, Medis medical imaging systems, Leiden, Netherlands). Angiographic measurements were made in the same 2 projections at pre- and post–procedure. The following QCA parameters were computed: stent length, reference vessel diameter, minimal lumen area and % diameter stenosis. After enrolment patients remained in hospital for at least 48 hours. Blood samples were drawn every 8 hours for the first 24 hours after randomization and daily afterwards for the determination of cardiac biomarkers. Daily recording of ECG was also performed until discharge. All patients were evaluated at 4 months by phone or office visit. OCT surveillance was scheduled for all patients at 4 months. Data were collected and entered into a computer database by specialized personnel of the Clinical Data Management Centre. All events were adjudicated and classified by an event adjudication committee blinded to the treatment groups. Myocardial infarction was defined as previously reported . Target lesion revascularization (TLR) was defined as any ischemia-driven repeat PCI of the target lesion or bypass surgery of the target vessel. Stent thrombosis was classified according to Academic Research Consortium (ARC) criteria.

2.3

OCT acquisition and analysis

Primary endpoint was the difference in rate of uncovered struts between BP-SES and EES assessed by OCT at 4 months post index intervention. Secondary endpoints were rate of malapposed struts, strut-level intimal thickness, and percent neointimal hyperplasia obstruction. Following administration of intravenous heparin and intracoronary nitrates OCT was performed using frequency domain OCT (C7XR system, LightLab Imaging, Westford, MA, USA) allowing acquisition at 100 frames per second with non-occlusive imaging technique. A standard guide wire was advanced distally in the target vessel and the OCT companion C7 Dragonfly™ catheter was advanced over the wire using rapid exchange technology. OCT imaging was performed at a pullback of 20 mm/s, during flush of 2–4 mL/s of iso-osmolar contrast through the guiding catheter to replace blood flow and permit visualization of the stented segment and intima-lumen interface. Scanning was prematurely terminated in case of haemodynamic instability, arrhythmia, or patient intolerance. If the stented segment was too long to be safely imaged in a single pullback, image acquisition was stopped and an additional pullback performed during a second contrast injection using anatomic landmarks such as side branches, calcifications for longitudinal view orientation.

Offline OCT data analysis was undertaken by an independent core laboratory (ISAR Center, Munich, Germany) blinded to stent-type allocation and clinical and procedural characteristics of the patients. Analysis of contiguous cross-sections at 1 mm longitudinal intervals within the stented segment was performed using proprietary software (LightLab imaging, Westford, MA, USA). Metallic stent struts typically appear as bright, signal-intense structures (blooming) with dorsal shadowing. A strut was considered suitable for analysis only if it had, 1) well defined bright ‘blooming’ appearance, and 2) characteristic shadow perpendicular to the light source. The number of stent struts was determined in each cross-section. Thickness (μm) of the tissue coverage in the luminal side of each strut was measured at the middle of the long axis of the strut. The inner and outer contours of each strut reflection were delineated for each strut and its distance to the lumen contour was calculated automatically to determine strut-level intimal thickness. Struts covered by tissue had positive strut-level intimal thickness values ≥ minimal axial resolution of OCT (20 μm), while struts were classified as malapposed if protruding into the lumen at a distance greater than the sum of the strut and polymer thickness (115 μm for the BP-SES and 89 μm for the EES) plus the minimal axial resolution of OCT (20 μm). Lumen area, stent area, neointimal area and percent area stenosis were assessed for every analyzed frame in the same manner. Neointimal hyperplasia volume was calculated, as appropriate . Non-analyzable frames were defined as frames in which greater than 45° of the lumen border was not visualized (e.g. due to presence of side branch) or with severe artifacts (e.g. due to inadequate blood clearance or non-uniform rotation distortion). In case of non-analyzable frames, an alternative frame of appropriate image quality within the next following or preceding two frames with appropriate image quality was analyzed. To summarize the spatial distribution of the neointimal coverage on the struts along the stents, ‘spread-out-vessel graphics’ were created by correlating the longitudinal distance from the distal edge of the stent to the strut (abscises) with the angle where the struts were located in the circular cross-section section respect to the center of gravity of the vessel (ordinates). The resultant graphic represented the stented vessel, as if it had been cut longitudinally along the reference angle 0° and spread out on a flat surface.

2.4

Statistical analysis

The objective of this pilot study was to compare the rapid breakdown biodegradable polymer sirolimus-eluting stent with the durable polymer everolimus-eluting stents regarding uncovered stent strut at 4-month follow-up assessed by OCT. The null hypothesis was that there would be no difference between the 2 stents in terms of stent strut coverage. We assumed a percentage of strut segments not covered by neointima of 4.5% for the BP-SES and 9% for the EES, representing a 50% relative reduction compared to the EES. With a 2-sided α-level of 0.05 and power of 90% we estimated that a total of 20 patients were required to be enrolled taking into account possible losses to follow-up. Sample size calculation was performed without adjustment for intrapatient clustering. The analysis of primary and secondary endpoints was planned on an intention-to-treat basis. Data are presented as values and percentages or mean value ± standard deviation or median and interquartile range (IQR). Categorical variables were compared with the Fisher’s exact test. Continuous variables were compared using the Welch’s t-test and Mann-Whitney U test based on the distribution. To take into account the clustered nature of the data, generalized linear mixed model approach was conducted for strut-level analysis comparison between patients with BP-SES and patients with EES with patient indicator (patient and frame) as a random effect and type of stent as a fixed effect. All analyses were performed with the use of R 2.15.1 (The R foundation for Statistical Computing, Vienna, Austria) and JMP 9.0.2 (SAS Institute Inc., Cary, NC). All statistical analyses were two-tailed and p values < 0.05 were considered statistically significant.

2.1

Study population, devices, randomization and intervention protocol

The P olymer Degrading-S i ro l imus Eluting-C o ronary Stent T rial (PILOT) was a prospective, multi-center pilot trial, enrolling a total of 20 patients, who were randomly assigned to treatment with either BP-SES or EES. Eligible patients (age, ≥ 18 years and < 80 years) had angina pectoris and/or objective signs of ischemia, in the presence of a ≥ 50% diameter stenosis de novo native coronary artery lesion. Key exclusion criteria included patients with cardiogenic shock, left ventricular function < 40%, presence of ≥ 2 target vessels or known hypersensitivity or allergy or contra-indication to contrast agents, aspirin, heparin, ticlopidine and clopidogrel. Lesions with excessive target lesion tortuosity, chronic total occlusion (older than 3 months), and ostial main vessel location were also excluded. The study complied with the declaration of Helsinki, was approved by all institutional ethics committees. All patients provided written informed consent for participation in the trial.

Allocation to treatment was made by means of sealed, opaque envelopes containing a computer-generated sequence. Randomization was performed after the decision to proceed with percutaneous coronary intervention and after crossing of the lesion with a guidewire. Patients who met all of the inclusion criteria and none of the exclusion criteria were randomised in the order that they qualified. Patients were assigned to receive BP-SES (ITRIX, AMG International GmbH, RAesfeld, Borken, Germany) or EES (Xience, Abbott Vascular, Santa Rosa, CA, USA). The ITRIX biodegradable polymer sirolimus-eluting stent is a laser-cut slotted tube stent with a multi-cellular architecture. After electropolishing and carbonizing, the stent is coated with a thin layer (5 μm) of biodegradable polymer, Poly dl -lactic-co-glycolic acid (PLGA). PLGA 50/50 is synthesized from polylactide and polyglycolide in 1:1 rate. The degradation process of this polymer is completed within 8 weeks and its degradation products (lactic and glycolic acid) are completely assimilated by human cell metabolism. The comparator EES is coated with everolimus at a dose of 100 μg/cm of stent surface and a non-biodegradable fluoropolymer, designed to release 80% of the everolimus in the first 30 days after deployment.

2.2

Data management, end points, and definitions

All patients had quantitative coronary angiograms (QCA) at baseline and immediately after PCI. Digital coronary angiograms were analyzed offline at the core laboratory (ISAR Center, Munich, Germany) with a validated automated edge detection system (QAngio XA v7.1, Medis medical imaging systems, Leiden, Netherlands). Angiographic measurements were made in the same 2 projections at pre- and post–procedure. The following QCA parameters were computed: stent length, reference vessel diameter, minimal lumen area and % diameter stenosis. After enrolment patients remained in hospital for at least 48 hours. Blood samples were drawn every 8 hours for the first 24 hours after randomization and daily afterwards for the determination of cardiac biomarkers. Daily recording of ECG was also performed until discharge. All patients were evaluated at 4 months by phone or office visit. OCT surveillance was scheduled for all patients at 4 months. Data were collected and entered into a computer database by specialized personnel of the Clinical Data Management Centre. All events were adjudicated and classified by an event adjudication committee blinded to the treatment groups. Myocardial infarction was defined as previously reported . Target lesion revascularization (TLR) was defined as any ischemia-driven repeat PCI of the target lesion or bypass surgery of the target vessel. Stent thrombosis was classified according to Academic Research Consortium (ARC) criteria.

2.3

OCT acquisition and analysis

Primary endpoint was the difference in rate of uncovered struts between BP-SES and EES assessed by OCT at 4 months post index intervention. Secondary endpoints were rate of malapposed struts, strut-level intimal thickness, and percent neointimal hyperplasia obstruction. Following administration of intravenous heparin and intracoronary nitrates OCT was performed using frequency domain OCT (C7XR system, LightLab Imaging, Westford, MA, USA) allowing acquisition at 100 frames per second with non-occlusive imaging technique. A standard guide wire was advanced distally in the target vessel and the OCT companion C7 Dragonfly™ catheter was advanced over the wire using rapid exchange technology. OCT imaging was performed at a pullback of 20 mm/s, during flush of 2–4 mL/s of iso-osmolar contrast through the guiding catheter to replace blood flow and permit visualization of the stented segment and intima-lumen interface. Scanning was prematurely terminated in case of haemodynamic instability, arrhythmia, or patient intolerance. If the stented segment was too long to be safely imaged in a single pullback, image acquisition was stopped and an additional pullback performed during a second contrast injection using anatomic landmarks such as side branches, calcifications for longitudinal view orientation.

Offline OCT data analysis was undertaken by an independent core laboratory (ISAR Center, Munich, Germany) blinded to stent-type allocation and clinical and procedural characteristics of the patients. Analysis of contiguous cross-sections at 1 mm longitudinal intervals within the stented segment was performed using proprietary software (LightLab imaging, Westford, MA, USA). Metallic stent struts typically appear as bright, signal-intense structures (blooming) with dorsal shadowing. A strut was considered suitable for analysis only if it had, 1) well defined bright ‘blooming’ appearance, and 2) characteristic shadow perpendicular to the light source. The number of stent struts was determined in each cross-section. Thickness (μm) of the tissue coverage in the luminal side of each strut was measured at the middle of the long axis of the strut. The inner and outer contours of each strut reflection were delineated for each strut and its distance to the lumen contour was calculated automatically to determine strut-level intimal thickness. Struts covered by tissue had positive strut-level intimal thickness values ≥ minimal axial resolution of OCT (20 μm), while struts were classified as malapposed if protruding into the lumen at a distance greater than the sum of the strut and polymer thickness (115 μm for the BP-SES and 89 μm for the EES) plus the minimal axial resolution of OCT (20 μm). Lumen area, stent area, neointimal area and percent area stenosis were assessed for every analyzed frame in the same manner. Neointimal hyperplasia volume was calculated, as appropriate . Non-analyzable frames were defined as frames in which greater than 45° of the lumen border was not visualized (e.g. due to presence of side branch) or with severe artifacts (e.g. due to inadequate blood clearance or non-uniform rotation distortion). In case of non-analyzable frames, an alternative frame of appropriate image quality within the next following or preceding two frames with appropriate image quality was analyzed. To summarize the spatial distribution of the neointimal coverage on the struts along the stents, ‘spread-out-vessel graphics’ were created by correlating the longitudinal distance from the distal edge of the stent to the strut (abscises) with the angle where the struts were located in the circular cross-section section respect to the center of gravity of the vessel (ordinates). The resultant graphic represented the stented vessel, as if it had been cut longitudinally along the reference angle 0° and spread out on a flat surface.

2.4

Statistical analysis

The objective of this pilot study was to compare the rapid breakdown biodegradable polymer sirolimus-eluting stent with the durable polymer everolimus-eluting stents regarding uncovered stent strut at 4-month follow-up assessed by OCT. The null hypothesis was that there would be no difference between the 2 stents in terms of stent strut coverage. We assumed a percentage of strut segments not covered by neointima of 4.5% for the BP-SES and 9% for the EES, representing a 50% relative reduction compared to the EES. With a 2-sided α-level of 0.05 and power of 90% we estimated that a total of 20 patients were required to be enrolled taking into account possible losses to follow-up. Sample size calculation was performed without adjustment for intrapatient clustering. The analysis of primary and secondary endpoints was planned on an intention-to-treat basis. Data are presented as values and percentages or mean value ± standard deviation or median and interquartile range (IQR). Categorical variables were compared with the Fisher’s exact test. Continuous variables were compared using the Welch’s t-test and Mann-Whitney U test based on the distribution. To take into account the clustered nature of the data, generalized linear mixed model approach was conducted for strut-level analysis comparison between patients with BP-SES and patients with EES with patient indicator (patient and frame) as a random effect and type of stent as a fixed effect. All analyses were performed with the use of R 2.15.1 (The R foundation for Statistical Computing, Vienna, Austria) and JMP 9.0.2 (SAS Institute Inc., Cary, NC). All statistical analyses were two-tailed and p values < 0.05 were considered statistically significant.