Temporal course of vascular healing and neoatherosclerosis after implantation of durable- or biodegradable-polymer drug-eluting stents

Temporal course of vascular healing and neoatherosclerosis after implantation of durable- or... Abstract Aims Delayed healing and endothelial dysfunction may occur with drug-eluting stents (DES), promoting accelerated infiltration of lipids in the neointima and development of neoatherosclerosis (NA). Pathology data suggest durable polymer (DP) of DES to play a major role in this process. Whether biodegradable polymer (BP) may address these issues is uncertain. We compared in vivo vessel healing and NA of current generation BP- or DP-DES using serial optical coherence tomography (OCT) assessments. Methods and results Ninety patients with multivessel coronary artery disease were randomized 1:1 to BP everolimus-eluting stents (EES, Synergy) or DP zotarolimus-eluting stents (ZES, Resolute Integrity). Co-primary endpoints were the maximum length of uncovered struts at 3 months (powered for non-inferiority) and the percentage of patients presenting with frames of NA at 18 months (powered for superiority) as measured by OCT. The maximum length of uncovered struts at 3 months was 10 ± 8 mm in the BP-EES group and 11 ± 7 mm in the DP-ZES group (mean difference −1 mm; upper 97.5% confidence interval +2 mm; P = 0.05 for non-inferiority; P = 0.45 for superiority). The percentage of patients presenting with frames of NA at 18 months was low and similar between BP-EES and DP-ZES groups (11.6% vs. 15.9%; P = 0.56). There was no stent thrombosis in both groups at 24 months. Conclusion BP-EES and DP-ZES showed a similar healing response at 3 months and a low incidence of NA at 18 months. Biocompatible polymers, regardless of whether they are durable or biodegradable, may favourably impact the long-term vascular response to current-generation DES. Drug-eluting stents , Biodegradable polymer , Optical coherence tomography Introduction Over the last decade, drug-eluting stents (DES) have undergone substantial modifications with thinner metallic struts and more biocompatible durable polymers (DP) or biodegradable polymers (BP). Taken together, these modifications have led to improved healing response and reduced thrombotic potential compared with earlier-generation DES, an effect amplified in patients with complex coronary artery disease.1–4 In this context, it is unclear to what extent BPs and DPs affect the short and long-term performance of current-generation DES with thin metallic struts. Poor strut coverage and in-stent neoatherosclerosis (NA) (i.e. the development of atherosclerotic changes within the stent neointima) are increasingly recognized mechanisms of late stent failure and major adverse cardiac events.5–7 Histopathology and intravascular imaging have detected NA earlier and more frequently with DES compared with bare metal stents, likely due to delayed healing and endothelial dysfunction that account for accelerated infiltration of lipids.8–10 Early NA development has been also reported with current-generation DES, thus becoming an important metric for comparative assessment of stent technologies. Importantly, the vascular response to DPs has been linked with NA progression. In fact, after drug elution has been completed, DP remnants may trigger local inflammatory vascular reactions and promote delayed healing, thus contributing to accelerated NA.11 To limit this risk, BPs that coat only the DES abluminal side and fully degrade after short-term delivery of the drug into the vessel wall have been developed. Whether abluminal BPs may be effective in counteracting the process of delayed healing and the development of early NA compared with conformal DPs is unknown. On this background, we sought to compare the short and long-term invivo vascular response of thin-strut current-generation DES coated with abluminal BP vs. conformal DP in unselected patients, using serial optical coherence tomography (OCT) imaging assessments. The ability of OCT to detect strut coverage and newly-onset atherosclerotic components within the stented segment provides a unique mean of investigating fine vascular responses to DES over time.12,13 Methods Study design and population The TRiple Assessment of Neointima Stent FOrmation to Reabsorbable polyMer With Optical Coherence Tomography (TRANSFORM-OCT) trial was a prospective, randomized, open-label, assessor-blinded, controlled study of patients with multivessel disease undergoing staged percutaneous coronary intervention (PCI) with stent implantation at two hospitals in Italy. Patients were eligible for the study if they presented with stable angina and documented ischaemia or acute coronary syndromes, including acute myocardial infarction with or without ST-segment elevation, and if they had at least two de novo lesions with >70% diameter stenosis located in separate coronary vessels amenable to PCI with stent implantation. By study protocol, ≥60% of the patients enrolled had to present with acute coronary syndromes. Major exclusion criteria were the presence of unprotected left main disease, chronic total occlusion, baseline serum creatinine >2.0 mg/dL, life expectancy <18 months, and unsuitability to OCT imaging (as per the investigator’s discretion). The full list of inclusion and exclusion criteria is provided in the Supplementary material online, Appendix. The study was designed and promoted by Ospedale Papa Giovanni XXIII (Bergamo, Italy), with unrestricted grant support provided by Boston Scientific Corporation (Marlborough, MA, USA). The company was not involved with any of the study processes, including data collection, analysis, drafting and approval of this article. The ethics committee at each participating centre approved the study, and all patients provided written informed consent for trial participation. The trial is registered in clinicaltrials.gov with the NCT01972022 identifier. Randomization After coronary angiography, eligible patients were randomly assigned 1:1 to receive either the abluminal BP everolimus-eluting stent (BP-EES, SYNERGY™, Boston Scientific Corporation, Marlborough, MA, USA) or the conformal DP zotarolimus-eluting stent (DP-ZES, RESOLUTE INTEGRITY, Medtronic Cardiovascular, Santa Rosa, CA, USA). The allocation sequence was generated by a web-based randomization system. Study devices The SYNERGY™ BP-EES consists of a platinum-chromium platform with thin struts (74 µm) coated only on the abluminal stent surface with an ultrathin (4 µm) BP made of polylactic-co-glycolic acid that elutes everolimus and degrades over a period of 3–4 months. The RESOLUTE INTEGRITY™ DP-ZES is a cobalt continuous sinusoid alloy with thin struts (89 µm) coated with a proprietary conformal (6 µm each side) DP named BioLinx that elutes zotarolimus. The two stents are available at the same diameters (2.25–4.0 mm) and in similar lengths (8–38 mm). Study procedures To allow serial OCT assessments at pre-defined time points, all PCI procedures were staged. The first lesion (i.e. culprit lesion in patients presenting with acute coronary syndromes, or most severe stenosis in patients with stable angina) was treated immediately after randomization (T0). Full lesion coverage was attempted by implantation of one or more allocated stents. The second lesion, located in a different coronary vessel, was stented with the same allocated stent at three months from randomization (T1). In patients with three-vessel disease, treatment and timing of treatment of additional lesions were left to the operator’s discretion based on clinical opportunity (i.e. location and severity) and could be performed either at T0 or at T1 with the same allocated stent. All stents were implanted according to standard techniques. Frequency domain OCT imaging of the first lesion was obtained before and immediately after stent implantation (T0), at 3 months (T1) and at 18 months from randomization (T2). OCT imaging of the second lesion was obtained at implant (T1) and at T2 (corresponding to 15 months from stent implantation). Details of the methodology for OCT imaging acquisition and following off-line analyses performed at an independent Core Laboratory (Harrington Heart & Vascular Institute, Cleveland, OH, USA) are reported in the Supplementary material online, Appendix . Adjunctive medications were given according to standard practice. Prior to stent implantation, patients received an intravenous bolus of heparin (70 UI/Kg) and 250 mg of intravenous aspirin. A loading dose of clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) was followed by maintenance doses of clopidogrel 75 mg od, prasugrel 10 mg od, or ticagrelor 90 mg bid, respectively, for 12 months. A high-intensity statin regimen (atorvastatin 80/40 mg or rosuvastatin 40/20 mg daily) was recommended to all patients. Adherence and lipid blood levels were monitored at 3 and 18 months (see Supplementary material online, AppendixTable S1). Serial clinical examinations were performed at 1-, 3-, 12-, and 24-month follow-up. Table 1 Baseline and procedural characteristics   BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06    BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06  BP, biodegradable-polymer; CABG, coronary artery bypass graft; CKD, chronic kidney disease; DP, durable-polymer; EES, everolimus-eluting stent; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; ZES, zotarolimus-eluting stent. Table 1 Baseline and procedural characteristics   BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06    BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06  BP, biodegradable-polymer; CABG, coronary artery bypass graft; CKD, chronic kidney disease; DP, durable-polymer; EES, everolimus-eluting stent; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; ZES, zotarolimus-eluting stent. Study organization All data were reported in electronic case report forms. Monitoring was performed by an independent contract research organization. Angiographic and OCT data collected at all time points were transferred to the independent imaging core laboratory for offline analyses. Readers at the core laboratory were blinded to the treatment groups. All clinical events were assessed and adjudicated by an independent clinical event and safety committee. Study endpoints Two co-primary OCT endpoints were defined: (i) maximum length of uncovered stent struts at 3 months and (ii) percentage of patients presenting with frames of in-stent NA at 18-month. Other metrics of interest were the percentage of covered and uncovered struts at 3 months (T1) and 18 months (T2), the percentage of apposed struts at post-implantation (T0) that presented without neointima at T1 and T2, the percentage and extent of newly acquired malapposed struts at T1 and T2, the mean neointimal thickness and the percentage of frames with evidence of mature neointimal coverage at T1 and T2. Clinical outcomes included major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of all-cause death, myocardial infarction, stroke and repeat revascularization, and related MACCE components up to 24-month follow-up (see Supplementary material online, Appendix). Optical coherence tomography definitions All OCT parameters were defined based on broadly accepted criteria as detailed in the Supplementary material online, Appendix. Briefly, neointima was defined as the tissue between the lumen and the inner border of the stent struts. In-stent NA was defined as the presence of any lipid-laden neointima, neointima with calcification, thin-cap fibroatheroma (TCFA) containing intima, neointimal rupture, intra-intimal neovascularization, and macrophage infiltration. The latter was defined as high-intensity luminal margin of the neointima, exceeding the intensity of background speckle noise, with strong light signal attenuation. Stent strut coverage and malapposition were defined and measured as described previously.14 Inter-observer and intra-observer variability The inter- and intra-observer k coefficient for detecting frame-based components of in-stent NA at 18 months was determined for a subset of 18 715 stented cross-sections with a mean neointima thickness >100 microns. The estimated inter- and intra-observer k coefficients were 0.85 and 0.88, respectively, for the presence of lipid-laden neointima, 0.91 and 0.92 for TCFA-containing intima, 1.00 for both neointimal rupture and neointima with calcification, 0.83 and 0.87 for neovascularization and 0.83 and 0.87 for macrophage infiltration. Statistical analysis We estimated that the random assignment of 82 patients and 82 lesions would provide 80% power (at a one-sided alpha level of 0.025) to show non-inferiority of BP-EES to DP-ZES with respect to the co-primary endpoint of maximal length of uncovered struts at 3 months, with a non-inferiority margin of 2 mm for the upper 97.5 confidence limit for the between-group difference in maximum length of uncovered struts, assuming an 8% rate of loss to follow-up or withdrawal from the trial. The non-inferiority margin was defined based on available data linking the longitudinal extension of uncovered struts with late DES thrombosis.15 With respect to the second co-primary endpoint (percentage of patients presenting with frames of NA at 18 months), we estimated that the random assignment of 88 patients and 88 lesions would provide 80% power (at a two-sided alpha level of 0.05) to show superiority of BP-EES to DP-ZES, assuming 50% patients with frames of NA in the DP-ZES group, 15% in the BP-EES group and 12% rate of loss to follow-up or withdrawal from the trial. The estimated percentage of patients presenting with frames of NA in the control group was based on human pathology data and invivo imaging studies available in the literature for selected groups of patients (e.g. symptomatic, in-stent restenosis, stent thrombosis).16,17 The primary analysis was performed with respect to the first lesion treated at T0 and followed up at T1 and T2. To account for the lower than anticipated percentage of patients with frames of NA, resulting in low statistical power for the assessment of the second co-primary endpoint, we conducted a sensitivity analysis using an expanded dataset including OCT data of the first lesion at T2 (18-month follow-up) and of the second lesion at T2 (15-month follow-up). To account for the clustered nature of data included in the expanded dataset (e.g. lesions nested within patients), generalized linear mixed models were used. All analyses were performed with SPSS (Statistical Package for Social Science, IBM) version 20 and SAS GLIMMIX (Statistical Analysis Software, SAS Institute Inc.) version 9.4. Continuous variables are reported as mean ± standard deviation. Categorical data are reported as counts and proportions. Comparisons between groups were based on unpaired Student t test for continuous variables (or Mann–Whitney U and Kruskal–Wallis tests in cases of significant departures from the normality assumption, namely P < 0.05 at the Kolmogorov–Smirnov or Shapiro–Wilks tests) and χ2 or Fisher’s exact tests for categorical variables (with the latter used when the expected cell count was <5). Statistical significance was set at the 0.05 alpha level. Results Baseline characteristics A total of 90 patients were randomized (45 allocated to the BP-EES group and 45 allocated to the DP-ZES group). Baseline clinical and angiographic characteristics were well balanced between the two groups (Table 1). Two- and three-vessel coronary artery disease was presents in 76% and 24% of patients, respectively. Acute coronary syndrome at time of presentation was present in 69% (N = 62), including 23% of patients presenting with ST-segment elevation myocardial infarction, and diabetes mellitus in 17% (N = 15). There were no differences between groups in lesion characteristics (Table 2 and Supplementary material online, AppendixTable S2), including pre-procedure minimal lumen area (MLA) at the target lesion site (1.6 ± 0.6 mm2 vs. 1.8 ± 0.9 mm2 in the BP-EES and DP-ZES groups, respectively; P = 0.18), proportion of lipid-rich frames at the MLA site (49 ± 31% vs. 46 ± 30%; P = 0.74) and lesion length (26 ± 11 mm vs. 24 ± 14 mm; P = 0.58). Table 2 Optical coherence tomography findings of the target lesion at the index procedure   BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99    BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; MLA, minimal lumen area; PCI, percutaneous coronary intervention; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. Table 2 Optical coherence tomography findings of the target lesion at the index procedure   BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99    BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; MLA, minimal lumen area; PCI, percutaneous coronary intervention; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. Procedural details At post-implant, there were no differences in the number of stents per target lesion (1.5 ± 0.7 vs. 1.4 ± 0.6; P = 0.40), total stent length (35 ± 14 mm vs. 33 ± 15 mm; P = 0.57), maximal inflation pressure (20 ± 4 atm vs. 22 ± 3 atm; P = 0.06), post-procedural mean stent area (7.8 ± 2.1 mm2 vs. 8.4 ± 2.3 mm2, P = 0.18), and percentage of struts embedded in the vessel wall (22 ± 14% vs. 19 ± 15%; P = 0.34). Three-month optical coherence tomography At 3 months, all randomized patients underwent angiographic and OCT follow-up (n = 90, 100%). The rates of covered, uncovered, uncovered and apposed struts were comparable between BP-EES and DP-ZES, with some degree of inter-individual variability in both groups (Table 3). The vast majority of uncovered struts were completely apposed to the vessel wall (85% in both groups). The maximum uncovered stent length (co-primary endpoint at 3 months) was 10 ± 8 mm in the BP-EES group and 11 ± 7 mm in the DP-ZES group (mean difference −1 mm; upper 97.5% confidence interval +2 mm; P = 0.05 for non-inferiority; P = 0.45 for superiority). A low and similar amount of neointimal thickness was measured (60 µm) in the BP-EES and DP-ZES groups (P = 0.61), with high percentage of neointimal frames with homogenous high-intensity signal pattern (89 ± 24% vs. 81 ± 28%; P = 0.21), representing mature neointimal tissue. No frames with any component of NA were detected at 3 months (Table 4). Table 3 Optical coherence tomography findings of struts coverage and neointimal response at different time intervals after stent implantation   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; NIH, neointimal hyperplasia; PCI, percutaneous coronary intervention; SD, standard deviation; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 3 months. Table 3 Optical coherence tomography findings of struts coverage and neointimal response at different time intervals after stent implantation   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; NIH, neointimal hyperplasia; PCI, percutaneous coronary intervention; SD, standard deviation; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 3 months. Table 4 Optical coherence tomography findings of neoatherosclerosis in neointima at different time points   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 18 months. Table 4 Optical coherence tomography findings of neoatherosclerosis in neointima at different time points   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 18 months. Eighteen-month optical coherence tomography Angiographic and OCT follow-up was available in 87 of 88 patients who were alive at 18 months (98.9%). Stent strut coverage was almost complete and similar in the BP-EES and DP-ZES groups (97 ± 7% vs. 95 ± 8%; P = 0.36) (Table 3). Compared with 3 months, a higher percentage of neointimal tissue covering the struts with homogeneous high-intensity signal characteristics was detected in both the BP-EES and DP-ZES groups (98 ± 6% vs. 100 ± 3%; P = 0.15) with negligible malapposition area (0 ± 0 mm2 vs. 0 ± 0.1 mm2; P = 0.22), and low amount of neointimal thickness (169 ± 67 µm vs. 143 ± 58 µm; P = 0.05). There was no difference between BP-EES and DP-ZES with respect to the percentage of covered struts, although there was a slightly higher maximum uncovered stent length with DP-ZES at 18 months (1.5 ± 2.0 vs. 2.6 ± 3.1; P = 0.04). The percentage of frames with NA was 1.1 ± 3.1% in the BP-EES group and 2.5 ± 9.1% in the DP-ZES group (P = 0.33). All single components suggestive of NA (e.g. lipid laden neointima, macrophages, calcium infiltration, TCFA and/or plaque rupture, peristrut neovascularization) were similarly and scarcely represented in the two groups (Table 4). The percentage of patients presenting frames of in-stent NA (co-primary endpoint) was not different between the BP-EES and DP-ZES groups (11.6% vs. 15.9%; P = 0.56). Neoatherosclerosis in the expanded dataset In the sensitivity analysis of the second co-primary endpoint, using OCT data of the first lesion at 18-month follow-up and of the second lesion at 15-month follow-up, the percentage of frames containing NA was evaluated using a generalized linear mixed model to account for the non-independence of the data. For BP-EES ad DP-ZES, the mean values were 1.7 ± 6.9% and 1.7 ± 7.0%, respectively (P = 0.77), consistent with the main analysis. Importantly, there were no differences in maximal length of uncovered struts between 15 and 18 months in both patients treated with BP-EES (1.4 ± 2.1 mm vs. 1.5 ± 2.0 mm, P > 0.05) and those treated with DP-ZES (2.6 ± 3.6 mm vs. 2.6 ± 3.1 mm, P > 0.05). Similarly, there were no differences in neointimal thickness between 15 and 18 months in patients treated with BP-EES (166 ± 59 µm vs. 169 ± 67 µm, P = 0.80) and those treated with DP-ZES (137 ± 53 µm vs. 143 ± 58 µm, P = 0.67). Further details on the vascular response of the first vs. the second lesion stratified by stent type are reported in the Supplementary material online, AppendixTable S3. Temporal course of vascular healing and neoatherosclerosis Take home figure summarizes (i) the serial distribution of strut coverage in BP-EES vs. DP-ZES across all study time points and (ii) the percentages of frames with NA and components of NA in BP-EES vs. DP-ZES at 18 months. Spread-out graphics from OCT-generated images at 3 months and 18 months, detailing clustering of uncovered struts and NA at the patient level along the stented regions, are shown in the Supplementary material online, Appendix Figures S1 and S2. Take home figure View largeDownload slide Upper left panel: schematic representation of heterogeneous vessel healing and atherosclerotic changes within the neointima at follow-up in stents with polymeric carrier. Upper right panel: Whisker plot summarizing the distribution of strut coverage of BP-EES and DP-ZES at post-procedure, 3 months and 18 months. No differences were observed between stent types at all time points. No differences were also noted in the maximal length of uncovered struts at 3 months, the 3-month co-primary endpoint of the study not shown here. Bottom panel: bar plot summarizing the proportion of patients with frames of neoatherosclerosis (left), the 18-month co-primary endpoint of the study, and components of neoatherosclerosis (right) at 18 months. No differences were observed between stent types at all time points. *Proportion of embedded struts was considered a surrogate of strut coverage at post-implant. BP-EES, biodegradable-polymer everolimus-eluting stent; DP-ZES, durable-polymer zotarolimus-eluting stent; PCI, percutaneous coronary intervention; TCFA, thin-cap fibroatheroma. Take home figure View largeDownload slide Upper left panel: schematic representation of heterogeneous vessel healing and atherosclerotic changes within the neointima at follow-up in stents with polymeric carrier. Upper right panel: Whisker plot summarizing the distribution of strut coverage of BP-EES and DP-ZES at post-procedure, 3 months and 18 months. No differences were observed between stent types at all time points. No differences were also noted in the maximal length of uncovered struts at 3 months, the 3-month co-primary endpoint of the study not shown here. Bottom panel: bar plot summarizing the proportion of patients with frames of neoatherosclerosis (left), the 18-month co-primary endpoint of the study, and components of neoatherosclerosis (right) at 18 months. No differences were observed between stent types at all time points. *Proportion of embedded struts was considered a surrogate of strut coverage at post-implant. BP-EES, biodegradable-polymer everolimus-eluting stent; DP-ZES, durable-polymer zotarolimus-eluting stent; PCI, percutaneous coronary intervention; TCFA, thin-cap fibroatheroma. Clinical outcomes The rates of MACCE and related components at 3 months and 24 months follow-up were low and similar in BP-EES and DP-ZES (see Supplementary material online, AppendixTable S4), with no episodes of cardiac death or stent thrombosis. Discussion The main findings of this study can be summarized as follows: (i) BP-EES and DP-ZES showed similar nominal values of maximal length of uncovered struts at 3 months, a surrogate OCT endpoint of early vascular healing; (ii) the incidence of NA at 18 months was lower than anticipated based on currently available pathology data, and similar between BP-EES and DP-ZES; and (iii) both stents showed excellent coverage rates at 18 months with a limited volume of neointima. Notably, these findings were obtained in vivo in a relatively complex population of patients undergoing PCI, comprising multivessel disease in all cases, and acute coronary syndromes in about two-thirds, on a background of high-intensity lipid lowering therapy. On the other hand, they might be not generalizable to patients with diabetes, which were under-represented in the study cohort, and to patients with renal failure, who were excluded. In aggregate, the results of the TRANSFORM-OCT trial add mechanistic insights to the understanding of the good safety profile of current-generation thin strut DESs, with no evidence of a differential effect attributable to the nature of the polymer (i.e. abluminal and biodegradable vs. conformal and durable). BPs were developed with the aim to enhance the vascular healing response to DES by eliminating the detrimental effects of DPs.18,19 However, DPs were also improved over time with development of more biocompatible carriers. Both devices compared in the present investigation feature thin struts, another factor deemed responsible of better vascular healing after PCI.20 It is not clear whether or not BP-DES may represent an advantage over DP-DES. Indeed, delayed healing associated with DPs has been linked to chronic local inflammation, development of NA and very late stent thrombosis, which sets the rationale for the present investigation.21 We designed the first randomized study comparing two currently available thin-struts DESs featuring different polymer designs with respect to their early and long-term invivo vascular response assessed by OCT imaging. Quantitative and qualitative OCT endpoints were measured in vivo serially over time and blindly analysed by an independent core laboratory to characterize the natural history of vessel healing and in-stent NA. OCT holds high accuracy for detecting strut coverage12 and identifies features of neointima transformation into atheromatous tissue.13 Early vascular response of durable- and biodegradable-polymer-drug-eluting stents At 3 months, no difference was found in terms of maximal longitudinal extension of uncovered struts. This OCT parameter was selected as co-primary endpoint based on multiple studies supporting its significant relationship with late and very late thrombosis of both first-generation and newer-generation DES.5,15,22 Importantly, assessing strut healing 3 months also allows for a fair comparison of BP-EES and DP-ZES at a time when the BP of the former is still in place. The confidence interval for the upper bound of the 95% confidence interval was 2 mm, coinciding with the pre-specified margin of non-inferiority. The P-value for non-inferiority was 0.05, which warrants cautious interpretation due to some chance for the study to be inconclusive due to a larger than anticipated confidence interval for the earlier co-primary endpoint. However, it should be noted that the difference in maximal uncovered struts length was marginal (−1 mm), with the direction of the estimate favouring the investigational study device. In addition, we found similarly mixed early coverage rates in both BP-EES and DP-ZES, both at the patient as well as the stent cross-section level (Take home figure and Supplementary material online, Appendix). Both stents presented with incomplete areas of coverage by OCT (see Supplementary material online, Appendix Figures S1 and S2), which raises a note of caution regarding the use of very short periods of DAPT in complex lesions and patients such as those represented in this study. Indeed, the spread-out graphics showed in the Supplementary material online, Appendix suggest that the patterns of early coverage of both DES considerably varied between patients and even within the same patient or lesion. That being said, strut uncoverage is not the only determinant of the risk of stent thrombosis. Indeed, the majority of uncovered struts were fully apposed or embedded into the vessel wall with a reassuring and comparable low incidence of incomplete strut apposition. Thin struts and high-pressure dilatation at the time of stent implantation may have factored in these observations. A small degree of neointima with homogeneous high-signal intensity imaging pattern, consistent with tissue maturation, was similarly found in both groups. No atherosclerotic changes of the neointimal tissue were observed within the stented segments at this early time point. Late vascular response of durable- and biodegradable-polymer-drug-eluting stents In-stent NA is considered an important contributing factor to long-term stent failure, representing a cause of both restenosis and late stent thrombosis.23 NA is more commonly detected by OCT in patients presenting with recurrence of symptoms and/or evidence of DES failure.17,24 In these patients, 90% of stented lesions with significant intimal hyperplasia (>50% of stent area) have lipid-containing neointima. In DES, the magnitude of lipid accumulation (expressed as the percentage of frames with lipid-laden neointima) is positively associated with the degree of neointimal hyperplasia.25 Our study, prospectively designed and conducted in relatively unselected patients, demonstrates a very low incidence and limited distribution of NA at 18 months in contemporary thin-strut DESs, coated with DPs or BPs. This was associated with OCT signs of almost complete vessel healing (with a borderline difference in maximum length of consecutive uncovered struts favouring BP-EES, paralleled by a slightly higher neointimal thickness), limited amount of neointima, and no cardiac death and/or stent thrombosis at 24-month follow-up. The rate of NA observed in our study was lower than anticipated by post-mortem data, probably reflecting a certain selection bias of pathology studies or the different resolution of pathology and OCT. Other contributing explanations are the small proportions of patients with diabetes and renal failure. In addition, it should be emphasized that our results were obtained in the context of patients on a high-intensity statin regimen. Therefore, we cannot rule out a differential vascular response in patients treated with a less intensive antilipidemic strategy. Indeed, retrospective observational studies using OCT at long-term follow-up and a recent multicentre registry comparing chronic angioscopy findings after DES implantation confirmed LDL-C levels to be independent predictors for in-stent NA.24,26 In our study, baseline LDL-C levels were promptly reduced by intensive statin therapy and remained effectively controlled over the 18-month observational time period (see Supplementary material online,Appendix Figure S3). Intriguingly, lower rates of low-intensity signal neointima (e.g. suggestive for lipid, fibrin or inflammation) were noted at 18 months compared with 3 months (Table 3). Although longer follow-up could be considered desirable to draw more definitive conclusions on the NA endpoint, the 18-month time window selected in this trial is consistent with pathology data describing NA at a median of 200–210 days for current generation DES.11,16 Limitations Some important limitations of this study must be acknowledged. First, it was an open-label study. Nevertheless, the two co-primary endpoints were adjudicated by an independent core-laboratory that was unaware of treatment allocation. Second, the stents compared in this study elute different antiproliferative drugs and differ in platform design (material and geometry), which might also have had impact on the results, regardless of the polymer characteristics. Third, the statistical assumption for sample size calculation was hampered by the lack of previous invivo OCT studies performed in unselected patients; therefore, our assumption on the percentage of NA at 18 months was necessarily arbitrary and based on reports of autopsy cases or OCT studies conducted in patients selected based on evidence of symptoms recurrence or stent failure. We observed a lower than anticipated percentage of NA at 18 months, which makes our study underpowered to draw a final conclusion regarding this endpoint with BP-EES and DP-ZES. However, identified differences in the occurrence of NA between groups were very low in absolute numbers, and a sensitivity analysis in an expanded dataset using data from other lesions assessed 15 months after stenting confirmed the results of the main analysis. Similarly, larger than expected variability for the primary endpoint of maximal length of uncovered struts at 3 months resulted in only borderline significance for the non-inferiority hypothesis, likely as the reflection of a power issue. Fourth, the study was not designed to investigate the clinical impact of OCT endpoints. Fifth, despite its unique axial resolution of few microns, OCT is not able to differentiate the complex changes of neointimal tissues at the histology level and cannot detect thin layers of re-generated endothelium. We used uncovered struts (percentage, maximum length of uncovered segment) by OCT as surrogate markers of delayed healing. In addition, because of the low penetration ability of OCT in lipid rich tissues, once the neointima becomes thickened it may be difficult to detect lipid changes. However, the small amount of neointimal thickness observed at 18 months in both stent types and the prevalent superficial location of in-stent atheroma (within 200 µm) reported by pathology do not raise major concerns on the ability of OCT to capture lipid changes or calcification close to the stent luminal site. Sixth, the known limitations of texture characterization of OCT imaging, including optical signal intensity and patterns of maturity, need to be taken into account.27 However, the homogeneous high intensity pattern mainly observed in both stents at all time points of follow-up holds a relatively high informative value for histological tissue components, overall representing maturing neointimal tissue.28 Finally, it remains unexplored whether longer-term OCT follow-up (i.e. >18 months) may reveal differential healing characteristics of contemporary DESs. Conclusions In this direct invivo comparison, the EES with bioresorbable abluminal polymer and the ZES with durable conformal polymer showed similar early and long-term healing response. In patients with complex coronary artery disease on an intensive statin regimen, excellent long-term vascular responses were observed in both stent types, with almost complete strut coverage, high percentage of mature tissue, limited neointimal deposition and low percentage of NA. This study consolidates the understanding that well designed and biocompatible polymers, regardless of whether they are durable or biodegradable, may favourably impact the long-term vascular response of DES. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements The authors thanks Francesca Fenili for her precious technical assistance, Audrey Schnell for her statistical counselling and the staff personnel of the cardiovascular department at participating sites for their invaluable support. Funding This study was designed, promoted and implemented by Ospedale Papa Giovanni XXIII, Bergamo, Italy, with unrestricted financial support provided by Boston Scientific Corporation. Conflict of interest: G.G. reports grants from Boston Scientific during the conduct of the present study. He is also consultant of St. Jude Medical and Boston Scientific and received institutional research grants from Abbott Vascular, Boston Scientific and St. Jude Medical. R.G. is a consultant of Terumo, Philips Volcano, IMDS, Alvimedica and received institutional research grants from Abbott Vascular, Asahi Intecc, Orbus Neich. G.B. is a consultant of Abbott Vascular and reports proctoring fees from Boston Scientific and St Jude Medical. F.C. received personal fees from Terumo and IMDS. G.F.A. reports consulting fees from Abbott Vascular, St. Jude Medical, Medtronic and Edwards. L.D.L. reports personal fees from Astra Zeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Daiichi Sankyo, Menarini and The Medicines Company. F.S. reports personal fees from Medtronic, Abbott Vascular, Boston Scientific, St. Jude, Volcano, Daiichi-Sankyo, Servier, and Menarini. D.C. reports consulting fees and speaker's honoraria from Abbott Vascular, Bayer, AstraZeneca, and Sanofi Aventis. All other authors report no conflict of interest. References 1 Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabaté M, Smits PC, Kaiser C, D'Ascenzo F, Frati G, Mancone M, Genereux P, Stone GW. Clinical outcomes with bioabsorbable polymer- versus durable polymer-based drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol  2014; 63: 299– 307. 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Abstract

Abstract Aims Delayed healing and endothelial dysfunction may occur with drug-eluting stents (DES), promoting accelerated infiltration of lipids in the neointima and development of neoatherosclerosis (NA). Pathology data suggest durable polymer (DP) of DES to play a major role in this process. Whether biodegradable polymer (BP) may address these issues is uncertain. We compared in vivo vessel healing and NA of current generation BP- or DP-DES using serial optical coherence tomography (OCT) assessments. Methods and results Ninety patients with multivessel coronary artery disease were randomized 1:1 to BP everolimus-eluting stents (EES, Synergy) or DP zotarolimus-eluting stents (ZES, Resolute Integrity). Co-primary endpoints were the maximum length of uncovered struts at 3 months (powered for non-inferiority) and the percentage of patients presenting with frames of NA at 18 months (powered for superiority) as measured by OCT. The maximum length of uncovered struts at 3 months was 10 ± 8 mm in the BP-EES group and 11 ± 7 mm in the DP-ZES group (mean difference −1 mm; upper 97.5% confidence interval +2 mm; P = 0.05 for non-inferiority; P = 0.45 for superiority). The percentage of patients presenting with frames of NA at 18 months was low and similar between BP-EES and DP-ZES groups (11.6% vs. 15.9%; P = 0.56). There was no stent thrombosis in both groups at 24 months. Conclusion BP-EES and DP-ZES showed a similar healing response at 3 months and a low incidence of NA at 18 months. Biocompatible polymers, regardless of whether they are durable or biodegradable, may favourably impact the long-term vascular response to current-generation DES. Drug-eluting stents , Biodegradable polymer , Optical coherence tomography Introduction Over the last decade, drug-eluting stents (DES) have undergone substantial modifications with thinner metallic struts and more biocompatible durable polymers (DP) or biodegradable polymers (BP). Taken together, these modifications have led to improved healing response and reduced thrombotic potential compared with earlier-generation DES, an effect amplified in patients with complex coronary artery disease.1–4 In this context, it is unclear to what extent BPs and DPs affect the short and long-term performance of current-generation DES with thin metallic struts. Poor strut coverage and in-stent neoatherosclerosis (NA) (i.e. the development of atherosclerotic changes within the stent neointima) are increasingly recognized mechanisms of late stent failure and major adverse cardiac events.5–7 Histopathology and intravascular imaging have detected NA earlier and more frequently with DES compared with bare metal stents, likely due to delayed healing and endothelial dysfunction that account for accelerated infiltration of lipids.8–10 Early NA development has been also reported with current-generation DES, thus becoming an important metric for comparative assessment of stent technologies. Importantly, the vascular response to DPs has been linked with NA progression. In fact, after drug elution has been completed, DP remnants may trigger local inflammatory vascular reactions and promote delayed healing, thus contributing to accelerated NA.11 To limit this risk, BPs that coat only the DES abluminal side and fully degrade after short-term delivery of the drug into the vessel wall have been developed. Whether abluminal BPs may be effective in counteracting the process of delayed healing and the development of early NA compared with conformal DPs is unknown. On this background, we sought to compare the short and long-term invivo vascular response of thin-strut current-generation DES coated with abluminal BP vs. conformal DP in unselected patients, using serial optical coherence tomography (OCT) imaging assessments. The ability of OCT to detect strut coverage and newly-onset atherosclerotic components within the stented segment provides a unique mean of investigating fine vascular responses to DES over time.12,13 Methods Study design and population The TRiple Assessment of Neointima Stent FOrmation to Reabsorbable polyMer With Optical Coherence Tomography (TRANSFORM-OCT) trial was a prospective, randomized, open-label, assessor-blinded, controlled study of patients with multivessel disease undergoing staged percutaneous coronary intervention (PCI) with stent implantation at two hospitals in Italy. Patients were eligible for the study if they presented with stable angina and documented ischaemia or acute coronary syndromes, including acute myocardial infarction with or without ST-segment elevation, and if they had at least two de novo lesions with >70% diameter stenosis located in separate coronary vessels amenable to PCI with stent implantation. By study protocol, ≥60% of the patients enrolled had to present with acute coronary syndromes. Major exclusion criteria were the presence of unprotected left main disease, chronic total occlusion, baseline serum creatinine >2.0 mg/dL, life expectancy <18 months, and unsuitability to OCT imaging (as per the investigator’s discretion). The full list of inclusion and exclusion criteria is provided in the Supplementary material online, Appendix. The study was designed and promoted by Ospedale Papa Giovanni XXIII (Bergamo, Italy), with unrestricted grant support provided by Boston Scientific Corporation (Marlborough, MA, USA). The company was not involved with any of the study processes, including data collection, analysis, drafting and approval of this article. The ethics committee at each participating centre approved the study, and all patients provided written informed consent for trial participation. The trial is registered in clinicaltrials.gov with the NCT01972022 identifier. Randomization After coronary angiography, eligible patients were randomly assigned 1:1 to receive either the abluminal BP everolimus-eluting stent (BP-EES, SYNERGY™, Boston Scientific Corporation, Marlborough, MA, USA) or the conformal DP zotarolimus-eluting stent (DP-ZES, RESOLUTE INTEGRITY, Medtronic Cardiovascular, Santa Rosa, CA, USA). The allocation sequence was generated by a web-based randomization system. Study devices The SYNERGY™ BP-EES consists of a platinum-chromium platform with thin struts (74 µm) coated only on the abluminal stent surface with an ultrathin (4 µm) BP made of polylactic-co-glycolic acid that elutes everolimus and degrades over a period of 3–4 months. The RESOLUTE INTEGRITY™ DP-ZES is a cobalt continuous sinusoid alloy with thin struts (89 µm) coated with a proprietary conformal (6 µm each side) DP named BioLinx that elutes zotarolimus. The two stents are available at the same diameters (2.25–4.0 mm) and in similar lengths (8–38 mm). Study procedures To allow serial OCT assessments at pre-defined time points, all PCI procedures were staged. The first lesion (i.e. culprit lesion in patients presenting with acute coronary syndromes, or most severe stenosis in patients with stable angina) was treated immediately after randomization (T0). Full lesion coverage was attempted by implantation of one or more allocated stents. The second lesion, located in a different coronary vessel, was stented with the same allocated stent at three months from randomization (T1). In patients with three-vessel disease, treatment and timing of treatment of additional lesions were left to the operator’s discretion based on clinical opportunity (i.e. location and severity) and could be performed either at T0 or at T1 with the same allocated stent. All stents were implanted according to standard techniques. Frequency domain OCT imaging of the first lesion was obtained before and immediately after stent implantation (T0), at 3 months (T1) and at 18 months from randomization (T2). OCT imaging of the second lesion was obtained at implant (T1) and at T2 (corresponding to 15 months from stent implantation). Details of the methodology for OCT imaging acquisition and following off-line analyses performed at an independent Core Laboratory (Harrington Heart & Vascular Institute, Cleveland, OH, USA) are reported in the Supplementary material online, Appendix . Adjunctive medications were given according to standard practice. Prior to stent implantation, patients received an intravenous bolus of heparin (70 UI/Kg) and 250 mg of intravenous aspirin. A loading dose of clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) was followed by maintenance doses of clopidogrel 75 mg od, prasugrel 10 mg od, or ticagrelor 90 mg bid, respectively, for 12 months. A high-intensity statin regimen (atorvastatin 80/40 mg or rosuvastatin 40/20 mg daily) was recommended to all patients. Adherence and lipid blood levels were monitored at 3 and 18 months (see Supplementary material online, AppendixTable S1). Serial clinical examinations were performed at 1-, 3-, 12-, and 24-month follow-up. Table 1 Baseline and procedural characteristics   BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06    BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06  BP, biodegradable-polymer; CABG, coronary artery bypass graft; CKD, chronic kidney disease; DP, durable-polymer; EES, everolimus-eluting stent; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; ZES, zotarolimus-eluting stent. Table 1 Baseline and procedural characteristics   BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06    BP-EES (N = 45)  DP-ZES (N = 45)  P-value  Baseline characteristics   Age (years) mean ± SD  64 ± 10  64 ± 10  0.47   Men, n (%)  33 (73)  39 (87)  0.11   Hypertension, n (%)  30 (67)  25 (56)  0.28   Hypercholesterolaemia, n (%)  23 (51)  18 (40)  0.29   Current smoker, n (%)  24 (53)  33 (73)  0.05   Diabetes mellitus, n (%)  7 (16)  8 (18)  0.77   Body mass index (kg/m2), mean ± SD  27 ± 3  27 ± 3  0.91   Previous myocardial infarction, n (%)  4 (9)  5 (11)  1.00   Previous PCI, n (%)  7 (16)  3 (7)  0.18   Previous CABG, n (%)  0 (0)  1 (2)  1.00   Previous stroke, n (%)  2 (4)  3 (7)  1.00   Indication for PCI, n (%)      0.65    Stable angina  13 (29)  15 (33)      Unstable angina  14 (31)  15 (33)      NSTEMI  4 (9)  6 (13)      STEMI  14 (31)  9 (20)     Number of diseased vessels, n (%)          2  35 (78)  33 (73)  0.62    3  10 (22)  12 (27)  0.48   Target vessel location, n (%)      0.54    Left anterior descending  23 (51)  21 (47)      Left circumflex  12 (27)  10 (22)      Right coronary artery  10 (22)  14 (31)    Procedural characteristics   Number of stents per lesion, mean ± SD  1.5 ± 0.7  1.4 ± 0.6  0.40   Total stent length (mm), mean ± SD  35 ± 14  33 ± 15  0.57   Stent diameter (mm), mean ± SD  3.1 ± 0.4  3.1 ± 0.4  0.58   Pre-dilation, n (%)  35 (78)  33 (73)  0.62   Post-dilation, n (%)  38 (84)  38 (84)  1.00   Maximal inflation pressure (atm), mean ± SD  20 ± 4  22 ± 3  0.06  BP, biodegradable-polymer; CABG, coronary artery bypass graft; CKD, chronic kidney disease; DP, durable-polymer; EES, everolimus-eluting stent; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; ZES, zotarolimus-eluting stent. Study organization All data were reported in electronic case report forms. Monitoring was performed by an independent contract research organization. Angiographic and OCT data collected at all time points were transferred to the independent imaging core laboratory for offline analyses. Readers at the core laboratory were blinded to the treatment groups. All clinical events were assessed and adjudicated by an independent clinical event and safety committee. Study endpoints Two co-primary OCT endpoints were defined: (i) maximum length of uncovered stent struts at 3 months and (ii) percentage of patients presenting with frames of in-stent NA at 18-month. Other metrics of interest were the percentage of covered and uncovered struts at 3 months (T1) and 18 months (T2), the percentage of apposed struts at post-implantation (T0) that presented without neointima at T1 and T2, the percentage and extent of newly acquired malapposed struts at T1 and T2, the mean neointimal thickness and the percentage of frames with evidence of mature neointimal coverage at T1 and T2. Clinical outcomes included major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of all-cause death, myocardial infarction, stroke and repeat revascularization, and related MACCE components up to 24-month follow-up (see Supplementary material online, Appendix). Optical coherence tomography definitions All OCT parameters were defined based on broadly accepted criteria as detailed in the Supplementary material online, Appendix. Briefly, neointima was defined as the tissue between the lumen and the inner border of the stent struts. In-stent NA was defined as the presence of any lipid-laden neointima, neointima with calcification, thin-cap fibroatheroma (TCFA) containing intima, neointimal rupture, intra-intimal neovascularization, and macrophage infiltration. The latter was defined as high-intensity luminal margin of the neointima, exceeding the intensity of background speckle noise, with strong light signal attenuation. Stent strut coverage and malapposition were defined and measured as described previously.14 Inter-observer and intra-observer variability The inter- and intra-observer k coefficient for detecting frame-based components of in-stent NA at 18 months was determined for a subset of 18 715 stented cross-sections with a mean neointima thickness >100 microns. The estimated inter- and intra-observer k coefficients were 0.85 and 0.88, respectively, for the presence of lipid-laden neointima, 0.91 and 0.92 for TCFA-containing intima, 1.00 for both neointimal rupture and neointima with calcification, 0.83 and 0.87 for neovascularization and 0.83 and 0.87 for macrophage infiltration. Statistical analysis We estimated that the random assignment of 82 patients and 82 lesions would provide 80% power (at a one-sided alpha level of 0.025) to show non-inferiority of BP-EES to DP-ZES with respect to the co-primary endpoint of maximal length of uncovered struts at 3 months, with a non-inferiority margin of 2 mm for the upper 97.5 confidence limit for the between-group difference in maximum length of uncovered struts, assuming an 8% rate of loss to follow-up or withdrawal from the trial. The non-inferiority margin was defined based on available data linking the longitudinal extension of uncovered struts with late DES thrombosis.15 With respect to the second co-primary endpoint (percentage of patients presenting with frames of NA at 18 months), we estimated that the random assignment of 88 patients and 88 lesions would provide 80% power (at a two-sided alpha level of 0.05) to show superiority of BP-EES to DP-ZES, assuming 50% patients with frames of NA in the DP-ZES group, 15% in the BP-EES group and 12% rate of loss to follow-up or withdrawal from the trial. The estimated percentage of patients presenting with frames of NA in the control group was based on human pathology data and invivo imaging studies available in the literature for selected groups of patients (e.g. symptomatic, in-stent restenosis, stent thrombosis).16,17 The primary analysis was performed with respect to the first lesion treated at T0 and followed up at T1 and T2. To account for the lower than anticipated percentage of patients with frames of NA, resulting in low statistical power for the assessment of the second co-primary endpoint, we conducted a sensitivity analysis using an expanded dataset including OCT data of the first lesion at T2 (18-month follow-up) and of the second lesion at T2 (15-month follow-up). To account for the clustered nature of data included in the expanded dataset (e.g. lesions nested within patients), generalized linear mixed models were used. All analyses were performed with SPSS (Statistical Package for Social Science, IBM) version 20 and SAS GLIMMIX (Statistical Analysis Software, SAS Institute Inc.) version 9.4. Continuous variables are reported as mean ± standard deviation. Categorical data are reported as counts and proportions. Comparisons between groups were based on unpaired Student t test for continuous variables (or Mann–Whitney U and Kruskal–Wallis tests in cases of significant departures from the normality assumption, namely P < 0.05 at the Kolmogorov–Smirnov or Shapiro–Wilks tests) and χ2 or Fisher’s exact tests for categorical variables (with the latter used when the expected cell count was <5). Statistical significance was set at the 0.05 alpha level. Results Baseline characteristics A total of 90 patients were randomized (45 allocated to the BP-EES group and 45 allocated to the DP-ZES group). Baseline clinical and angiographic characteristics were well balanced between the two groups (Table 1). Two- and three-vessel coronary artery disease was presents in 76% and 24% of patients, respectively. Acute coronary syndrome at time of presentation was present in 69% (N = 62), including 23% of patients presenting with ST-segment elevation myocardial infarction, and diabetes mellitus in 17% (N = 15). There were no differences between groups in lesion characteristics (Table 2 and Supplementary material online, AppendixTable S2), including pre-procedure minimal lumen area (MLA) at the target lesion site (1.6 ± 0.6 mm2 vs. 1.8 ± 0.9 mm2 in the BP-EES and DP-ZES groups, respectively; P = 0.18), proportion of lipid-rich frames at the MLA site (49 ± 31% vs. 46 ± 30%; P = 0.74) and lesion length (26 ± 11 mm vs. 24 ± 14 mm; P = 0.58). Table 2 Optical coherence tomography findings of the target lesion at the index procedure   BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99    BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; MLA, minimal lumen area; PCI, percutaneous coronary intervention; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. Table 2 Optical coherence tomography findings of the target lesion at the index procedure   BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99    BP-EES (N = 44)  DP-ZES (N = 45)  P-value  Pre-PCI   Lesion length (mm), mean ± SD  26 ± 11  24 ± 14  0.58   Mean reference vessel area (mm2), mean ± SD  7.4 ± 2.3  7.1 ± 2.8  0.59   Mean lumen area (mm2), mean ± SD  4.5 ± 1.3  4.9 ± 1.8  0.16   Minimal lumen area (mm2), mean ± SD  1.6 ± 0.6  1.8 ± 0.9  0.18   Percent area stenosis (% ), mean ± SD  77 ± 10  72 ± 15  0.14   Presence of plaque rupture, n (%)  12 (27)  12 (27)  0.16   Presence of plaque erosion, n (%)  1 (2)  6 (13)  0.11   Presence of TCFA, n (%)  27 (61)  27 (60)  0.90   Presence of thrombus, n (%)  16 (36)  24 (53)  0.11   Plaque constituents (%), mean ± SD          Calcified  10 ± 13  17 ± 20  0.06    Fibrous  49 ± 18  45 ± 18  0.29    Lipid  16 ± 15  17 ± 14  0.73    Normal  25 ± 20  21 ± 15  0.30   Plaque constituents at MLA-site (%), mean ± SD          Calcified  14 ± 23  15 ± 27  0.88    Fibrous  34 ± 27  37 ± 25  0.63    Lipid  49 ± 31  46 ± 30  0.74    Normal  10 ± 16  6 ± 12  0.29  Post-stent implantation, mean ± SD   Proximal reference vessel area (mm2)  9.4 ± 2.9  9.4 ± 2.9  0.90   Distal reference vessel area (mm2)  5.5 ± 2.8  5.3 ± 2.2  0.80   Mean stent area (mm2)  7.8 ± 2.1  8.4 ± 2.3  0.18   Minimal stent area (mm2)  5.7 ± 1.8  6.4 ± 2.2  0.12   Stent expansion index (%)  82 ± 20  86 ± 15  0.30   Analyzed stent length (mm)  34 ± 13  33 ± 15  0.68   Analyzed cross sections (n)  54 ± 21  52 ± 24  0.63   Struts analyzed per lesion (n)  427 ± 180  561 ± 292  0.01   Struts analyzed per cross section (n)  5 ± 1  7 ± 2  <0.001   Embedded struts (%)  22 ± 14  19 ± 15  0.34   Malapposed struts (%)  4 ± 4  5 ± 5  0.33   Mean malapposition area (mm2)  0.1 ± 0.1  0.1 ± 0.1  0.99  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; MLA, minimal lumen area; PCI, percutaneous coronary intervention; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. Procedural details At post-implant, there were no differences in the number of stents per target lesion (1.5 ± 0.7 vs. 1.4 ± 0.6; P = 0.40), total stent length (35 ± 14 mm vs. 33 ± 15 mm; P = 0.57), maximal inflation pressure (20 ± 4 atm vs. 22 ± 3 atm; P = 0.06), post-procedural mean stent area (7.8 ± 2.1 mm2 vs. 8.4 ± 2.3 mm2, P = 0.18), and percentage of struts embedded in the vessel wall (22 ± 14% vs. 19 ± 15%; P = 0.34). Three-month optical coherence tomography At 3 months, all randomized patients underwent angiographic and OCT follow-up (n = 90, 100%). The rates of covered, uncovered, uncovered and apposed struts were comparable between BP-EES and DP-ZES, with some degree of inter-individual variability in both groups (Table 3). The vast majority of uncovered struts were completely apposed to the vessel wall (85% in both groups). The maximum uncovered stent length (co-primary endpoint at 3 months) was 10 ± 8 mm in the BP-EES group and 11 ± 7 mm in the DP-ZES group (mean difference −1 mm; upper 97.5% confidence interval +2 mm; P = 0.05 for non-inferiority; P = 0.45 for superiority). A low and similar amount of neointimal thickness was measured (60 µm) in the BP-EES and DP-ZES groups (P = 0.61), with high percentage of neointimal frames with homogenous high-intensity signal pattern (89 ± 24% vs. 81 ± 28%; P = 0.21), representing mature neointimal tissue. No frames with any component of NA were detected at 3 months (Table 4). Table 3 Optical coherence tomography findings of struts coverage and neointimal response at different time intervals after stent implantation   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; NIH, neointimal hyperplasia; PCI, percutaneous coronary intervention; SD, standard deviation; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 3 months. Table 3 Optical coherence tomography findings of struts coverage and neointimal response at different time intervals after stent implantation   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients, 18 317 struts)  DP-ZES (N = 45 patients, 25 290 struts)  P-value  BP-EES (N = 43 patients, 17 092 struts)  DP-ZES (N = 44 patients, 25 170 struts)  P-value  Minimal stent area (mm2), mean ± SD  5.8 ± 1.8  6.5 ± 2.1  0.08  5.8 ± 1.8  6.4 ± 1.9  0.11  Minimal lumen area (mm2), mean ± SD  5.4 ± 2.0  6.1 ± 2.3  0.16  4.4 ± 1.8  5.1 ± 2.1  0.07  Analysed stent length (mm), mean ± SD  34 ± 13  32 ± 14  0.58  34 ± 13  33 ± 15  0.72  Analysed cross sections (n), mean ± SD  52 ± 20  49 ± 22  0.58  51 ± 20  50 ± 23  0.82  Struts analysed per lesion (n), mean ± SD  407 ± 156  562 ± 263  0.001  398 ± 147  572 ± 259  <0.001   Covered struts (%), mean ± SD  73 ± 20  73 ± 17  0.87  97 ± 7  95 ± 8  0.36   Uncovered struts (%), mean ± SD  27 ± 20  26 ± 17  0.87  4 ± 7  5 ± 8  0.46   Uncovered and apposed struts (%), mean ± SD  23 ± 17  23 ± 15  0.99  3 ± 7  4 ± 6  0.46   Maximal length of uncovered segment (mm), mean ± SDa  10 ± 8  11 ± 7  0.45  1.5 ± 2.0  2.6 ± 3.1  0.04   Malapposed struts (%), mean ± SD  4.2 ± 6.1  3.5 ± 4.8  0.56  0.4 ± 1.2  0.9 ± 2.7  0.30   Mean malapposition area (mm2), mean ± SD  0.2 ± 0.2  0.1 ± 0.2  0.16  0.0 ± 0.0  0.0 ± 0.1  0.22   Maximal length of malapposed segment (mm), mean ± SD  2.7 ± 3.2  3.1 ± 3.2  0.52  0.3 ± 0.8  0.6 ± 1.2  0.27   Late acquired malapposed struts (%), mean ± SD  1.2 ± 2.4  0.7 ± 1.6  0.25  0.1 ± 0.5  0.3 ± 2.0  0.58  Mean NIH thickness (µm), mean ± SD  60 ± 32  60 ± 33  0.61  169 ± 67  143 ± 58  0.05  Qualitative neointimal characterization               Frames with homogeneous high signal pattern neointima (%), mean ± SD  89 ± 24  81 ± 28  0.21  98 ± 6  100 ± 3  0.15   Frames with any low signal pattern neointima (%), mean ± SD  11 ± 24  20 ± 28  0.21  2 ± 6  0.5 ± 2.5  0.15  Quantitative neointimal optical properties               Minimum normalized signal intensity (n), mean ± SD  0.6 ± 0.1  0.6 ± 0.1  0.26  0.7 ± 0.2  0.6 ± 0.2  0.24   Mean normalized signal intensity (n), mean ± SD  0.7 ± 0.1  0.7 ± 0.0  0.61  0.8 ± 0.0  0.8 ± 0.1  0.24  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; NIH, neointimal hyperplasia; PCI, percutaneous coronary intervention; SD, standard deviation; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 3 months. Table 4 Optical coherence tomography findings of neoatherosclerosis in neointima at different time points   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 18 months. Table 4 Optical coherence tomography findings of neoatherosclerosis in neointima at different time points   3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54    3-Month follow-up   18-Month follow-up   BP-EES (N = 45 patients)  DP-ZES (N = 45 patients)  P-value  BP-EES (N = 43 patients)  DP-ZES (N = 44 patients)  P-value  Frequency of patients with neoatherosclerosis in neointima, n (%)a  0 (0)  0 (0)  —  11.6 (5)  15.9 (7)  0.56  Cross-section level analysis               Frequency of neoatherosclerosis in neointima (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  1.1 ± 3.1  2.5 ± 9.1  0.33    Lipid rich plaque (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.8 ± 2.5  2.4 ± 9.0  0.24    Calcification (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Macrophage (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.1 ± 0.8  0.32    TCFA (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.5 ± 3.2  0.32    Plaque rupture (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.0 ± 0.0  0.0 ± 0.0  —    Neovascularization (%), mean ± SD  0.0 ± 0.0  0.0 ± 0.0  —  0.3 ± 2.0  0.1 ± 0.6  0.54  BP, biodegradable-polymer; DP, durable-polymer; EES, everolimus-eluting stent; SD, standard deviation; TCFA, thin-cap fibroatheroma; ZES, zotarolimus-eluting stent. a Co-primary endpoint at 18 months. Eighteen-month optical coherence tomography Angiographic and OCT follow-up was available in 87 of 88 patients who were alive at 18 months (98.9%). Stent strut coverage was almost complete and similar in the BP-EES and DP-ZES groups (97 ± 7% vs. 95 ± 8%; P = 0.36) (Table 3). Compared with 3 months, a higher percentage of neointimal tissue covering the struts with homogeneous high-intensity signal characteristics was detected in both the BP-EES and DP-ZES groups (98 ± 6% vs. 100 ± 3%; P = 0.15) with negligible malapposition area (0 ± 0 mm2 vs. 0 ± 0.1 mm2; P = 0.22), and low amount of neointimal thickness (169 ± 67 µm vs. 143 ± 58 µm; P = 0.05). There was no difference between BP-EES and DP-ZES with respect to the percentage of covered struts, although there was a slightly higher maximum uncovered stent length with DP-ZES at 18 months (1.5 ± 2.0 vs. 2.6 ± 3.1; P = 0.04). The percentage of frames with NA was 1.1 ± 3.1% in the BP-EES group and 2.5 ± 9.1% in the DP-ZES group (P = 0.33). All single components suggestive of NA (e.g. lipid laden neointima, macrophages, calcium infiltration, TCFA and/or plaque rupture, peristrut neovascularization) were similarly and scarcely represented in the two groups (Table 4). The percentage of patients presenting frames of in-stent NA (co-primary endpoint) was not different between the BP-EES and DP-ZES groups (11.6% vs. 15.9%; P = 0.56). Neoatherosclerosis in the expanded dataset In the sensitivity analysis of the second co-primary endpoint, using OCT data of the first lesion at 18-month follow-up and of the second lesion at 15-month follow-up, the percentage of frames containing NA was evaluated using a generalized linear mixed model to account for the non-independence of the data. For BP-EES ad DP-ZES, the mean values were 1.7 ± 6.9% and 1.7 ± 7.0%, respectively (P = 0.77), consistent with the main analysis. Importantly, there were no differences in maximal length of uncovered struts between 15 and 18 months in both patients treated with BP-EES (1.4 ± 2.1 mm vs. 1.5 ± 2.0 mm, P > 0.05) and those treated with DP-ZES (2.6 ± 3.6 mm vs. 2.6 ± 3.1 mm, P > 0.05). Similarly, there were no differences in neointimal thickness between 15 and 18 months in patients treated with BP-EES (166 ± 59 µm vs. 169 ± 67 µm, P = 0.80) and those treated with DP-ZES (137 ± 53 µm vs. 143 ± 58 µm, P = 0.67). Further details on the vascular response of the first vs. the second lesion stratified by stent type are reported in the Supplementary material online, AppendixTable S3. Temporal course of vascular healing and neoatherosclerosis Take home figure summarizes (i) the serial distribution of strut coverage in BP-EES vs. DP-ZES across all study time points and (ii) the percentages of frames with NA and components of NA in BP-EES vs. DP-ZES at 18 months. Spread-out graphics from OCT-generated images at 3 months and 18 months, detailing clustering of uncovered struts and NA at the patient level along the stented regions, are shown in the Supplementary material online, Appendix Figures S1 and S2. Take home figure View largeDownload slide Upper left panel: schematic representation of heterogeneous vessel healing and atherosclerotic changes within the neointima at follow-up in stents with polymeric carrier. Upper right panel: Whisker plot summarizing the distribution of strut coverage of BP-EES and DP-ZES at post-procedure, 3 months and 18 months. No differences were observed between stent types at all time points. No differences were also noted in the maximal length of uncovered struts at 3 months, the 3-month co-primary endpoint of the study not shown here. Bottom panel: bar plot summarizing the proportion of patients with frames of neoatherosclerosis (left), the 18-month co-primary endpoint of the study, and components of neoatherosclerosis (right) at 18 months. No differences were observed between stent types at all time points. *Proportion of embedded struts was considered a surrogate of strut coverage at post-implant. BP-EES, biodegradable-polymer everolimus-eluting stent; DP-ZES, durable-polymer zotarolimus-eluting stent; PCI, percutaneous coronary intervention; TCFA, thin-cap fibroatheroma. Take home figure View largeDownload slide Upper left panel: schematic representation of heterogeneous vessel healing and atherosclerotic changes within the neointima at follow-up in stents with polymeric carrier. Upper right panel: Whisker plot summarizing the distribution of strut coverage of BP-EES and DP-ZES at post-procedure, 3 months and 18 months. No differences were observed between stent types at all time points. No differences were also noted in the maximal length of uncovered struts at 3 months, the 3-month co-primary endpoint of the study not shown here. Bottom panel: bar plot summarizing the proportion of patients with frames of neoatherosclerosis (left), the 18-month co-primary endpoint of the study, and components of neoatherosclerosis (right) at 18 months. No differences were observed between stent types at all time points. *Proportion of embedded struts was considered a surrogate of strut coverage at post-implant. BP-EES, biodegradable-polymer everolimus-eluting stent; DP-ZES, durable-polymer zotarolimus-eluting stent; PCI, percutaneous coronary intervention; TCFA, thin-cap fibroatheroma. Clinical outcomes The rates of MACCE and related components at 3 months and 24 months follow-up were low and similar in BP-EES and DP-ZES (see Supplementary material online, AppendixTable S4), with no episodes of cardiac death or stent thrombosis. Discussion The main findings of this study can be summarized as follows: (i) BP-EES and DP-ZES showed similar nominal values of maximal length of uncovered struts at 3 months, a surrogate OCT endpoint of early vascular healing; (ii) the incidence of NA at 18 months was lower than anticipated based on currently available pathology data, and similar between BP-EES and DP-ZES; and (iii) both stents showed excellent coverage rates at 18 months with a limited volume of neointima. Notably, these findings were obtained in vivo in a relatively complex population of patients undergoing PCI, comprising multivessel disease in all cases, and acute coronary syndromes in about two-thirds, on a background of high-intensity lipid lowering therapy. On the other hand, they might be not generalizable to patients with diabetes, which were under-represented in the study cohort, and to patients with renal failure, who were excluded. In aggregate, the results of the TRANSFORM-OCT trial add mechanistic insights to the understanding of the good safety profile of current-generation thin strut DESs, with no evidence of a differential effect attributable to the nature of the polymer (i.e. abluminal and biodegradable vs. conformal and durable). BPs were developed with the aim to enhance the vascular healing response to DES by eliminating the detrimental effects of DPs.18,19 However, DPs were also improved over time with development of more biocompatible carriers. Both devices compared in the present investigation feature thin struts, another factor deemed responsible of better vascular healing after PCI.20 It is not clear whether or not BP-DES may represent an advantage over DP-DES. Indeed, delayed healing associated with DPs has been linked to chronic local inflammation, development of NA and very late stent thrombosis, which sets the rationale for the present investigation.21 We designed the first randomized study comparing two currently available thin-struts DESs featuring different polymer designs with respect to their early and long-term invivo vascular response assessed by OCT imaging. Quantitative and qualitative OCT endpoints were measured in vivo serially over time and blindly analysed by an independent core laboratory to characterize the natural history of vessel healing and in-stent NA. OCT holds high accuracy for detecting strut coverage12 and identifies features of neointima transformation into atheromatous tissue.13 Early vascular response of durable- and biodegradable-polymer-drug-eluting stents At 3 months, no difference was found in terms of maximal longitudinal extension of uncovered struts. This OCT parameter was selected as co-primary endpoint based on multiple studies supporting its significant relationship with late and very late thrombosis of both first-generation and newer-generation DES.5,15,22 Importantly, assessing strut healing 3 months also allows for a fair comparison of BP-EES and DP-ZES at a time when the BP of the former is still in place. The confidence interval for the upper bound of the 95% confidence interval was 2 mm, coinciding with the pre-specified margin of non-inferiority. The P-value for non-inferiority was 0.05, which warrants cautious interpretation due to some chance for the study to be inconclusive due to a larger than anticipated confidence interval for the earlier co-primary endpoint. However, it should be noted that the difference in maximal uncovered struts length was marginal (−1 mm), with the direction of the estimate favouring the investigational study device. In addition, we found similarly mixed early coverage rates in both BP-EES and DP-ZES, both at the patient as well as the stent cross-section level (Take home figure and Supplementary material online, Appendix). Both stents presented with incomplete areas of coverage by OCT (see Supplementary material online, Appendix Figures S1 and S2), which raises a note of caution regarding the use of very short periods of DAPT in complex lesions and patients such as those represented in this study. Indeed, the spread-out graphics showed in the Supplementary material online, Appendix suggest that the patterns of early coverage of both DES considerably varied between patients and even within the same patient or lesion. That being said, strut uncoverage is not the only determinant of the risk of stent thrombosis. Indeed, the majority of uncovered struts were fully apposed or embedded into the vessel wall with a reassuring and comparable low incidence of incomplete strut apposition. Thin struts and high-pressure dilatation at the time of stent implantation may have factored in these observations. A small degree of neointima with homogeneous high-signal intensity imaging pattern, consistent with tissue maturation, was similarly found in both groups. No atherosclerotic changes of the neointimal tissue were observed within the stented segments at this early time point. Late vascular response of durable- and biodegradable-polymer-drug-eluting stents In-stent NA is considered an important contributing factor to long-term stent failure, representing a cause of both restenosis and late stent thrombosis.23 NA is more commonly detected by OCT in patients presenting with recurrence of symptoms and/or evidence of DES failure.17,24 In these patients, 90% of stented lesions with significant intimal hyperplasia (>50% of stent area) have lipid-containing neointima. In DES, the magnitude of lipid accumulation (expressed as the percentage of frames with lipid-laden neointima) is positively associated with the degree of neointimal hyperplasia.25 Our study, prospectively designed and conducted in relatively unselected patients, demonstrates a very low incidence and limited distribution of NA at 18 months in contemporary thin-strut DESs, coated with DPs or BPs. This was associated with OCT signs of almost complete vessel healing (with a borderline difference in maximum length of consecutive uncovered struts favouring BP-EES, paralleled by a slightly higher neointimal thickness), limited amount of neointima, and no cardiac death and/or stent thrombosis at 24-month follow-up. The rate of NA observed in our study was lower than anticipated by post-mortem data, probably reflecting a certain selection bias of pathology studies or the different resolution of pathology and OCT. Other contributing explanations are the small proportions of patients with diabetes and renal failure. In addition, it should be emphasized that our results were obtained in the context of patients on a high-intensity statin regimen. Therefore, we cannot rule out a differential vascular response in patients treated with a less intensive antilipidemic strategy. Indeed, retrospective observational studies using OCT at long-term follow-up and a recent multicentre registry comparing chronic angioscopy findings after DES implantation confirmed LDL-C levels to be independent predictors for in-stent NA.24,26 In our study, baseline LDL-C levels were promptly reduced by intensive statin therapy and remained effectively controlled over the 18-month observational time period (see Supplementary material online,Appendix Figure S3). Intriguingly, lower rates of low-intensity signal neointima (e.g. suggestive for lipid, fibrin or inflammation) were noted at 18 months compared with 3 months (Table 3). Although longer follow-up could be considered desirable to draw more definitive conclusions on the NA endpoint, the 18-month time window selected in this trial is consistent with pathology data describing NA at a median of 200–210 days for current generation DES.11,16 Limitations Some important limitations of this study must be acknowledged. First, it was an open-label study. Nevertheless, the two co-primary endpoints were adjudicated by an independent core-laboratory that was unaware of treatment allocation. Second, the stents compared in this study elute different antiproliferative drugs and differ in platform design (material and geometry), which might also have had impact on the results, regardless of the polymer characteristics. Third, the statistical assumption for sample size calculation was hampered by the lack of previous invivo OCT studies performed in unselected patients; therefore, our assumption on the percentage of NA at 18 months was necessarily arbitrary and based on reports of autopsy cases or OCT studies conducted in patients selected based on evidence of symptoms recurrence or stent failure. We observed a lower than anticipated percentage of NA at 18 months, which makes our study underpowered to draw a final conclusion regarding this endpoint with BP-EES and DP-ZES. However, identified differences in the occurrence of NA between groups were very low in absolute numbers, and a sensitivity analysis in an expanded dataset using data from other lesions assessed 15 months after stenting confirmed the results of the main analysis. Similarly, larger than expected variability for the primary endpoint of maximal length of uncovered struts at 3 months resulted in only borderline significance for the non-inferiority hypothesis, likely as the reflection of a power issue. Fourth, the study was not designed to investigate the clinical impact of OCT endpoints. Fifth, despite its unique axial resolution of few microns, OCT is not able to differentiate the complex changes of neointimal tissues at the histology level and cannot detect thin layers of re-generated endothelium. We used uncovered struts (percentage, maximum length of uncovered segment) by OCT as surrogate markers of delayed healing. In addition, because of the low penetration ability of OCT in lipid rich tissues, once the neointima becomes thickened it may be difficult to detect lipid changes. However, the small amount of neointimal thickness observed at 18 months in both stent types and the prevalent superficial location of in-stent atheroma (within 200 µm) reported by pathology do not raise major concerns on the ability of OCT to capture lipid changes or calcification close to the stent luminal site. Sixth, the known limitations of texture characterization of OCT imaging, including optical signal intensity and patterns of maturity, need to be taken into account.27 However, the homogeneous high intensity pattern mainly observed in both stents at all time points of follow-up holds a relatively high informative value for histological tissue components, overall representing maturing neointimal tissue.28 Finally, it remains unexplored whether longer-term OCT follow-up (i.e. >18 months) may reveal differential healing characteristics of contemporary DESs. Conclusions In this direct invivo comparison, the EES with bioresorbable abluminal polymer and the ZES with durable conformal polymer showed similar early and long-term healing response. In patients with complex coronary artery disease on an intensive statin regimen, excellent long-term vascular responses were observed in both stent types, with almost complete strut coverage, high percentage of mature tissue, limited neointimal deposition and low percentage of NA. This study consolidates the understanding that well designed and biocompatible polymers, regardless of whether they are durable or biodegradable, may favourably impact the long-term vascular response of DES. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements The authors thanks Francesca Fenili for her precious technical assistance, Audrey Schnell for her statistical counselling and the staff personnel of the cardiovascular department at participating sites for their invaluable support. Funding This study was designed, promoted and implemented by Ospedale Papa Giovanni XXIII, Bergamo, Italy, with unrestricted financial support provided by Boston Scientific Corporation. Conflict of interest: G.G. reports grants from Boston Scientific during the conduct of the present study. He is also consultant of St. Jude Medical and Boston Scientific and received institutional research grants from Abbott Vascular, Boston Scientific and St. Jude Medical. R.G. is a consultant of Terumo, Philips Volcano, IMDS, Alvimedica and received institutional research grants from Abbott Vascular, Asahi Intecc, Orbus Neich. G.B. is a consultant of Abbott Vascular and reports proctoring fees from Boston Scientific and St Jude Medical. 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European Heart JournalOxford University Press

Published: May 19, 2018

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