Randomized comparison of sirolimus eluting, and biolimus eluting bioresorbable polymer stents: the SORT-OUT VII optical coherence tomography study

Randomized comparison of sirolimus eluting, and biolimus eluting bioresorbable polymer stents:... Abstract Aims To show non-inferiority of the 67- or 87 µm thick, sirolimus-eluting Orsiro drug eluting stent (DES) to the 122 µm thick, biolimus-eluting Nobori DES regarding size of vessel lumen outside the stent at 13-month follow-up. Methods and results This study was a substudy to the SORT-OUT VII trial, a prospective, 1:1-randomized, comparison of the two stents in patients with stable coronary artery disease or acute coronary syndrome. Optical coherence tomography was acquired after percutaneous coronary intervention and at 13-month follow-up. The substudy was powered to access non-inferiority (Δ = 0.60 mm2) of the Orsiro DES to the Nobori DES for the primary endpoint of mean extra stent lumen (ESL) i.e. vessel lumen outside the stent at 13-month follow-up. We randomized 124 patients to Orsiro (n = 60) or Nobori (n = 64). Due to a difference in the one-sided 95%-confidence interval of 0.26 mm2, but increased to 0.82 mm2 after appropriate log-transformation, it could not be rejected that Orsiro exceeded the non-inferiority limit. Testing for superiority, Orsiro had a significantly larger mean ESL at follow-up (Orsiro: 0.11 mm2 [0.02;0.30] mm2, Nobori: 0.03 mm2 [0.00;0.17] mm2, P = 0.04). Stent strut coverage was, Orsiro: 97.6 % [93.8;99.4]%, and Nobori: 96.3 % [90.5;98,6]% (P = 0.13). Conclusion Orsiro DES had a significantly larger mean ESL at follow-up and it could not be excluded that Orsiro exceeded the limit for non-inferiority. Nobori DES had a more heterogeneous distribution of neointima but stent strut coverage did not differ significantly between the two stents. drug-eluting stents , bioresorbable polymer stents , optical coherence tomography Introduction First generation coronary drug eluting stents (DES) with permanent polymers are associated with increased risk of late- and very late stent thrombosis (ST) when compared with bare metal stents (BMS).1,2 Underlying pathologic mechanisms include hypersensitivity reactions towards the polymer, resulting in delayed vessel healing with incomplete neointimal coverage and aneurysmatic changes of the vessel wall.3–5 Newer generation DES designed with biocompatible polymers improved the DES safety profile,6 and latest generation DES with thinner stent platforms and biodegradable polymers were aimed to improve early healing and reduce the risk of adverse long-term reactions.7 Differences in stent platforms, biocompatibility, and degradation pace of polymers may influence healing patterns.8 The purpose of this study was to compare 13-month stent performance and vessel wall healing response, evaluated by optical coherence tomography (OCT), after implantation of the 67–87 µm thick, sirolimus-eluting Orsiro DES (Biotronik, Germany), and a 122 µm thick biolimus-eluting Nobori DES (Terumo, Jp) in patients with stable angina pectoris (SAP) or acute coronary syndrome (ACS). Methods Study design The SORT-OUT VII OCT study was a substudy to the clinical SORT-OUT VII trial (NCT01879358), a prospective, randomized, multi-centre, all-comer trial, enrolling 2525 patients. The substudy was conducted at Odense University Hospital and Aarhus University Hospital, Denmark. The OCT substudy was notified after first enrollment in the main SORT-OUT VII study. Randomization was stratified by gender and diabetes, and participation in the OCT substudy. Patients eligible for the substudy were included with a planned target of 120 patients. Patients were randomized 1:1 to receive either sirolimus-eluting Orsiro DES (BiotronikTM, Berlin, Germany) or biolimus-eluting Nobori DES (Terumo CorporationTM, Tokyo, Japan). Randomization was stratified by sex and diabetes, and participation in the OCT substudy. OCT was performed immediately after percutaneous coronary intervention (PCI) and at 13-month follow-up. The study included patients aged ≥ 18 years with stable—or unstable coronary artery disease, ST-segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI), and at least one coronary lesion with more than 50% diameter stenosis. Exclusion criteria for this substudy were aorto-ostial lesions, s-creatinine > 120µmol/L, severely tortuous target coronary artery, life expectancy less than 1 year, allergy to aspirin, clopidogrel, ticagrelor, prasugrel, sirolimus, or biolimus. The main SORT-OUT VII trial and the SORT-OUT VII OCT substudy were approved by The Central Denmark Region Committees on Health Research Ethics. All patients provided written informed consent for participation in the trial (NCT01879358). Study stents The CE-certified Orsiro DES is designed with a permanent thin ‘ProBIO’ coating aimed at reducing ion-release, and a poly-l-lactic acid biodegradable polymer eluting sirolimus during the first 12–14 weeks. The polymer is almost completely degraded within 1–2 years. The stent features two different platform designs; a small size (diameters 2.25 to 3.0 mm, strut thickness 60  + 7 µm polymer) and a larger size (diameters 3.5 to 4.0 mm, strut thickness 80 + 7 µm polymer).9 The CE-certified Nobori DES is based on a stainless steel platform with a thin permanent parylene coating, and a biodegradable polymer coating of the abluminal side of struts. The polymer elutes biolimus A9 (Biosensors International, Singapore) for the first approximately 30 days during the polymer degradation lasting 6–9 months. Strut thickness is 112 + 10 μm polymer.10 Study procedure Medical treatment and PCI was performed according to standard procedures as previously described.11 Use of pre-dilatation of the lesion, direct stenting or post-dilatation of the stent was decided by the PCI-operator, OCT could be used for evaluating the procedure at the discretion of the operator, and the baseline OCT-recording was performed as the final intervention before removing the guide wire. OCT acquisition OCT imaging was performed using the St. Jude Medical OCT-system (Illumien™ or Illumien OPTISTM) and a C7 Dragonfly™ catheter (St. Jude Medical, Minnesota, MN, USA) after intracoronary administration of nitroglycerine. OCT images were recorded at either 100 frames per second (fps) with a catheter pullback speed of 20 mm/s, or 180 fps with pullback speed 18 or 36 mm/s during flushing with contrast. Clinical follow-up and endpoints Clinical endpoints included all-cause mortality, cardiac death, myocardial infarction (MI), ST, and target lesion revascularization (TLR). The endpoints were obtained from health registries covering from discharge until 13-month angiography. Additional clinical endpoint definitions were described in the SORT-OUT VII main study.11 OCT analysis OCT acquired post-PCI and at 13-month follow-up were matched at frame-level and analysed by blinded observers using off-line semi-automated analysis software (QCU-CMS Research, Leiden, The Netherlands). The entire stent segment, including the margins 5 mm proximal and distal to the stent, were evaluated in all consecutive frames for recording quality, plaque type and extend, and thrombus. Thrombus was defined as an irregular mass appearing in the lumen with or without attachment to the vessel wall (Figure 1C). Quantitative OCT analysis was performed at 0.5 or 0.6 mm intervals after calibration of the OCT recordings. Lumen and stent contours, and areas were measured. At follow-up, tissue coverage was evaluated visually for each strut and neointimal thickness (NIT) was measured as the shortest distance from the centre of the strut blooming signal to the lumen border (Figure 1D). Struts were considered malapposed when the smallest distance from the centre of the leading strut blooming signal to the lumen contour exceeded the sum of the strut thickness + polymer + 20 µm (Figure 1F). Clusters of malapposed struts were defined as 10 counts of malapposed struts within five or less consecutive frames. At follow-up, clusters were classified into persistent, abolished or acquired. Figure 1 View largeDownload slide Endpoint illustration—A Extra stent lumen (ESL): lumen area outside stent, indicated by the red area. B Maximum ESL: the largest total area outside the stent in one frame. B1: Maximum ESL at frame level: area outside stent limited by two apposed struts, indicated by the yellow delineated area. C Thrombus: irregular mass appearing in the lumen. D Neointimal thickness (NIT): shortest distance from the centre of the strut to the lumen boarder. E Coverage: verified visible tissue on struts. F Malapposed strut. Clusters of malapposed struts defined as 10 counts of malapposed struts within five or less consecutive frames. Figure 1 View largeDownload slide Endpoint illustration—A Extra stent lumen (ESL): lumen area outside stent, indicated by the red area. B Maximum ESL: the largest total area outside the stent in one frame. B1: Maximum ESL at frame level: area outside stent limited by two apposed struts, indicated by the yellow delineated area. C Thrombus: irregular mass appearing in the lumen. D Neointimal thickness (NIT): shortest distance from the centre of the strut to the lumen boarder. E Coverage: verified visible tissue on struts. F Malapposed strut. Clusters of malapposed struts defined as 10 counts of malapposed struts within five or less consecutive frames. Primary and secondary endpoints (OCT) The primary endpoint of mean extra stent lumen (ESL) was evaluated by OCT at 13-month follow-up. ESL was defined as lumen area outside the stent contour (Figure 1A). Secondary endpoints included change in mean ESL from baseline to follow-up. Maximum ESL was measured and defined as the largest total area outside stent in one frame (Figure 1B). Maximum ESL at frame level was defined as the maximal area outside stent limited by two apposed struts (Figure 1B, B1). Additional secondary endpoints were malapposition at baseline and at 13-month follow-up, persistent-, abolished-, or acquired malapposed clusters, stent area late loss (late recoil), minimal lumen area (MLA), neointimal thickness (NIT), thrombus on stent struts at baseline, in-stent thrombus at follow-up and mean neointimal area calculated and measured as the area delineated abluminal by the stent contour and luminal by the lumen contour. Sample size Experience by treatment with the sirolimus eluting Cypher stent has demonstrated that evaginations and aneurysm formation are reflected in an increased maximum ESL of 0.60 ± 0.83 mm2 at a mean 1-year follow-up.12 The mean ESL area was estimated to be 0.30 mm2 and a non-inferiority margin of 0.60 mm2 was decided as the clinically acceptable difference. With an assumed standard deviation of 1.0 mm2 and a power of 90% the estimated numbers of patients required were 96 patients. By including 120 patients 20% could be lost to follow-up. Statistics Continuous variables are presented as mean ± standard deviation if following a Gaussian distribution or alternatively as median and inter-quartile range. Non-parametric data are presented as absolute numbers and percentages. Differences in characteristics between the two DES were compared using Student’s t-test or Mann–Whitney test as appropriate. χ2 test was used for comparing categorical variables, alternative Fisher’s exact test in case of cell values less than 5. Due to a non-normal distribution of the primary endpoint data of mean ESL at 13-month, several transformations were made to find the most appropriate transformation (log (ESL + 0.001)). Median values and confidence intervals (CI) of the transformed analysis were back transformed and compared with the preplanned analysis to evaluate if non-inferiority of Orsiro DES to Nobori DES was met. Statistical significance was accepted for P-values < 0.05. All statistical analyses were performed using STATA version 13 (STATA Inc., College Station, TX). Results We included 124 randomized patients in the OCT substudy between June 2013 and February 2014. Sixty patients were treated with the Orsiro DES, while 64 patients were treated with the Nobori DES. Clinical follow-up at 13-month was available in all patients. Baseline characteristics were well balanced between the two groups, except for treatment indication, which varied between stable- and unstable angina pectoris between the two groups (Table 1). All patients received the allocated study stent. Almost 15% of the patients in both groups had diabetes. The most frequently treated vessel in both groups was LAD (Orsiro: 55%, Nobori: 50%, P = 0.52) (Table 2). Table 1 Baseline characteristics   Orsiro DES  Nobori DES  P-value  No. of patients  60  64    Age (year)  61 ± 9.3  60 ± 10.4  0.81  Male gender  50 (83%)  52 (81%)  0.76  Diabetes  9 (15%)  10 (16%)  0.93  Systolic blood pressure (mmHg)  142 ± 20  138 ± 22  0.29  Diastolic blood pressure (mmHg)  79 ± 11  78 ± 12  0.72  Hypertension treatment  25 (42%)  27 (42%)  0.95  Current smoker  19 (32%)  20 (33%)  0.90  Ischaemic heart disease in family  33 (59%)  30 (49%)  0.29  Statin treatment  37 (62%)  34 (53%)  0.34  Previous CABG  1 (2%)  2 (3%)  1.00  Previous PCI  11 (18%)  6 (9%)  0.15  Previous AMI  9 (15%)  5 (8%)  0.21  Previous heart operation  1 (2%)  2 (3%)  1.00  BMI (kg/m2)  27.9 ± 4.9  26.9 ± 4.1  0.22  Indication      0.04  Stable angina pectoris  27 (45%)  38 (59%)    Unstable angina pectoris  9 (15%)  1 (2%)    NSTEMI  15 (25%)  14 (22%)    STEMI  9 (15%)  11 (17%)    Baseline OCT characteristics  No. of patients  45  43  88  Mean lumen area (mm2)  8.1 ± 2.3  8.8 ± 3.0  0.22  Mean stent area (mm2)  8.5 ± 2.3  9.2 ± 3.0  0.23  Thrombus on struts, per patient level (n)  31 (69%)  27 (63%)  0.65    Orsiro DES  Nobori DES  P-value  No. of patients  60  64    Age (year)  61 ± 9.3  60 ± 10.4  0.81  Male gender  50 (83%)  52 (81%)  0.76  Diabetes  9 (15%)  10 (16%)  0.93  Systolic blood pressure (mmHg)  142 ± 20  138 ± 22  0.29  Diastolic blood pressure (mmHg)  79 ± 11  78 ± 12  0.72  Hypertension treatment  25 (42%)  27 (42%)  0.95  Current smoker  19 (32%)  20 (33%)  0.90  Ischaemic heart disease in family  33 (59%)  30 (49%)  0.29  Statin treatment  37 (62%)  34 (53%)  0.34  Previous CABG  1 (2%)  2 (3%)  1.00  Previous PCI  11 (18%)  6 (9%)  0.15  Previous AMI  9 (15%)  5 (8%)  0.21  Previous heart operation  1 (2%)  2 (3%)  1.00  BMI (kg/m2)  27.9 ± 4.9  26.9 ± 4.1  0.22  Indication      0.04  Stable angina pectoris  27 (45%)  38 (59%)    Unstable angina pectoris  9 (15%)  1 (2%)    NSTEMI  15 (25%)  14 (22%)    STEMI  9 (15%)  11 (17%)    Baseline OCT characteristics  No. of patients  45  43  88  Mean lumen area (mm2)  8.1 ± 2.3  8.8 ± 3.0  0.22  Mean stent area (mm2)  8.5 ± 2.3  9.2 ± 3.0  0.23  Thrombus on struts, per patient level (n)  31 (69%)  27 (63%)  0.65  Table 2 Procedural characteristics   Orsiro DES  Nobori DES  P-value  N  60  64    Number of stents  1.1 ± 0.4  1.3 ± 0.7  0.08  Nominal stent length (mm)  20.5 ± 7.6  24.4 ± 12.9  0.18  Lesions length (mm)  16.0 ± 6.9  18.1 ± 9.6  0.47  Max. balloon diameter (mm)  3.6 ± 0.5  3.5 ± 0.5  0.91  Max. balloon pressure (mmHg)  16.1 ± 3.5  16.5 ± 3.7  0.50  Reference diameter (visual estimate) (mm)  3.5 ± 0.5  3.4 ± 0.5  0.73  Reference diameter(combined OCT and QCA) (mm)  3.6 ± 0.6  3.6 ± 0.7  0.76  Treated vessel        RCA  18 (30%)  21 (33%)  0.56  LAD  33 (55%)  32 (50%)  0.52  LCA  9 (15%)  11 (17%)  0.56    Orsiro DES  Nobori DES  P-value  N  60  64    Number of stents  1.1 ± 0.4  1.3 ± 0.7  0.08  Nominal stent length (mm)  20.5 ± 7.6  24.4 ± 12.9  0.18  Lesions length (mm)  16.0 ± 6.9  18.1 ± 9.6  0.47  Max. balloon diameter (mm)  3.6 ± 0.5  3.5 ± 0.5  0.91  Max. balloon pressure (mmHg)  16.1 ± 3.5  16.5 ± 3.7  0.50  Reference diameter (visual estimate) (mm)  3.5 ± 0.5  3.4 ± 0.5  0.73  Reference diameter(combined OCT and QCA) (mm)  3.6 ± 0.6  3.6 ± 0.7  0.76  Treated vessel        RCA  18 (30%)  21 (33%)  0.56  LAD  33 (55%)  32 (50%)  0.52  LCA  9 (15%)  11 (17%)  0.56  Clinical results At 13-month clinical follow-up, NSTEMI occurred in one of 60 patients in the Orsiro group and one of 64 patients in the Nobori group. No patients had stent thrombosis. One patient treated with a Nobori DES suffered non-cardiac death. OCT 13-month follow-up results OCT follow-up was available in 88 patients (Figure 2). The primary outcome measure of difference in mean ESL at 13-month between the two stent groups was mean 0.12 mm2 with a one-sided 95%-CI of 0.26 mm2. Result after appropriate log-transformation yielded a one-sided 95%-CI up to 0.82 mm2. With this difference in CI, we could not reject that Orsiro exceeded the non-inferiority limit (0.60 mm2): see Figure 3B. Testing for superiority, the median ESL at 13-month follow-up was 0.11 mm2 [0.02;0.30] mm2 for the Orsiro DES and 0.03 mm2 [0.00;0.17] mm2 for the Nobori DES (P = 0.04) (Figure 3A). Orsiro DES showed a significant larger increase in mean ESL from baseline to 13-month compared with the Nobori DES (0.006 mm2 [−0.012;0.160] mm2 vs. −0.017mm2 [−0.060;0.012] mm2, P = 0.01) (Figure 3C). The significant difference in favour of Nobori DES was confirmed by sensitivity analysis excluding two cases in the Orsiro arm with large aneurysms (Figures 3A, 5B and C). Figure 2 View largeDownload slide Patient flow chart—AMI, acute myocardial infarction; DES, drug eluting stent; FU, follow-up; OCT, optical coherence tomography. Figure 2 View largeDownload slide Patient flow chart—AMI, acute myocardial infarction; DES, drug eluting stent; FU, follow-up; OCT, optical coherence tomography. Figure 3 View largeDownload slide Endpoint plots—A Primary endpoint of mean extra stent lumen (ESL) at 13-month follow-up. B 95%-Confidence interval (CI) for non-transformed data and log (ESL + 0.001) transformed data showing difference in non-inferiority margin. C Baseline corrected mean ESL. The significant difference in favour of Nobori DES was confirmed by sensitivity analysis excluding two cases with mayor aneurysms in the Orsiro arm. D Difference in malapposition vs. difference in mean ESL. Red box indicate patients with a decrease in amount of mallapposed struts but an increase in mean ESL. Figure 3 View largeDownload slide Endpoint plots—A Primary endpoint of mean extra stent lumen (ESL) at 13-month follow-up. B 95%-Confidence interval (CI) for non-transformed data and log (ESL + 0.001) transformed data showing difference in non-inferiority margin. C Baseline corrected mean ESL. The significant difference in favour of Nobori DES was confirmed by sensitivity analysis excluding two cases with mayor aneurysms in the Orsiro arm. D Difference in malapposition vs. difference in mean ESL. Red box indicate patients with a decrease in amount of mallapposed struts but an increase in mean ESL. Coverages and neointimal thickness NIT The median percentage of covered struts was similar in the two groups (97.6% [93.8;99.4] % (Orsiro DES), 96.3% [90.5;98.69] % (Nobori DES), (P = 0.13)). A total of 6 patients (13%) in the Orsiro treated group and 9 patients (21%) treated with a Nobori DES showed coverage levels below 90% after 13-month (Figure 4A). The median NIT was 70.8 µm [62.8;96.7] µm in the Orsiro group and 74.6 µm [62.9;114.8] µm in the Nobori group (P = 0.43). The median neointimal area was significant larger for the Nobori DES (1.28 mm2 [0.96;1.68] mm2 vs. Orsiro: 0.92 mm2 [0.70;1.13] mm2, P = 0.0001) (Figure 4B and C). Figure 4 View largeDownload slide Secondary endpoints—A Stent strut coverage. Coverage below 90% was found in 13% in the Orsiro group vs. 21% in the Nobori group. B Mean neointimal thickness (NIT). No siginifcant difference between the two DESs. C Mean neointimal area. Significant larger area for the Nobori DES (1.28 mm2) than for the Orsiro DES (0.92 mm2) (P = 0.001). Figure 4 View largeDownload slide Secondary endpoints—A Stent strut coverage. Coverage below 90% was found in 13% in the Orsiro group vs. 21% in the Nobori group. B Mean neointimal thickness (NIT). No siginifcant difference between the two DESs. C Mean neointimal area. Significant larger area for the Nobori DES (1.28 mm2) than for the Orsiro DES (0.92 mm2) (P = 0.001). Malapposition At baseline, malapposed struts were found in 2.9% [0.4;10.0] % and 2.1% [0.7;6.8] % of analysed struts in the Orsiro, and the Nobori DES respectively (P = 0.66). At 13-month follow-up, malapposition was 0.0% [0.0;1.1] % (Orsiro DES) and 0.0% [0.0;0.5] % (Nobori DES), (P = 0.37). We found no difference in number of patients with clustered baseline malapposition; 24 patients with a total of 37 clusters in the Orsiro group compared with 19 patients with a total of 30 clusters in the Nobori group (P = 0.39). Clusters of acquired malapposition at follow-up were found in four patients (9%) in the Orsiro group and two patients (5%) in the Nobori group (P = 0.68). Number of patients having clusters of persistent or resolved of malapposed clusters did not differ between the stents (Orsiro: 6 patients (13%), Nobori: 2 patients (5%), P = 0.27 and Orsiro: 20 patients (44%), Nobori: 18 patients (42%), P = 0.81, respectively (Supplementary data online, Table S1). Lumen size and stent properties Baseline minimal lumen area (MLA) was 6.55 mm2 (Orsiro) and 7.07 mm2 (Nobori) (P = 0.28), while minimal stent area (MSA) was 7.04 mm2 (Orsiro) and 7.62 mm2 (Nobori) (P = 0.26). Additional baseline properties are shown in Table 1. Mean lumen area late loss was significantly larger in the Nobori than in the Orsiro group (Nobori: 0.74  ± 0.82 mm2, Orsiro: 0.07 ± 1.06 mm2, P = 0.001), while MLA late loss did not differ statistically significantly (0.75  ± 1.06 mm2 vs. 0.47 ± 1.16 mm2, P = 0.25). Late stent recoil was only identified for Nobori (0.19 ± 0.85 mm2. Orsiro: −0.12 ± 0.89 mm2). Additional secondary endpoint results are shown in Table 3. Table 3 Primary and secondary endpoints   Orsiro DES  Nobori DES  P-value  Extra stent lumen area at 13 month follow-up (mm2)  0.11 [0.02;0.30]  0.03 [0.00;0.17]  0.04  Extra stent lumen area at baseline (mm2)  0.05 [0.01;0.13]  0.04 [0.02;0.14]  0.81  Extra stent lumen area enhancement (mm2)  0.006 [−0.01;0.16]  −0.017 [−0.06;0.01]  0.01  Maximal ESL        Baseline (mm2)  0.57 [0.14;1.07]  0.39 [0.13;1.14]  0.74  Follow-up (mm2)  1.01 [0.18;1.70]  0.43 [0.05;1.08]  0.11  Difference (mm2)  0.07 [−0.11;0.92]  −0.09 [−0.50;0.38]  0.11  Maximal ESL at frame level        Baseline (mm2)  0.46 [0.12;1.07]  0.38 [0.13;1.10]  0.72  Follow-up (mm2)  0.59 [0.14;1.45]  0.37 [0.04;1.04]  0.16  Difference (mm2)  0.02 [−0.16;0.47]  −0.09 [−0.50;0.33]  0.14  Mean lumen area (mm2)  8.1 ± 2.7  8.1 ± 3.1  0.97  Minimal lumen area (mm2)  6.1 ± 2.2  6.3 ± 2.7  0.64  Mean stent area (mm2)  8.8 ± 2.5  9.3 ± 3.1  0.39  Mean stent area late loss (mm2)  −0.3 ± 0.7  −0.1 ± 0.5  0.21  Minimal stent area (mm2)  7.1 ± 2.3  7.4 ± 2.7  0.49  Mean neointimal area (mm2)  1.0 ± 0.4  1.4 ± 0.5  0.0002  Neointima/stent area (%)  11.6 ± 4.7  15.8 ± 7.0  0.001  Stents with thrombus at follow-up (n)  7 (16%)  5 (12%)  0.76    Orsiro DES  Nobori DES  P-value  Extra stent lumen area at 13 month follow-up (mm2)  0.11 [0.02;0.30]  0.03 [0.00;0.17]  0.04  Extra stent lumen area at baseline (mm2)  0.05 [0.01;0.13]  0.04 [0.02;0.14]  0.81  Extra stent lumen area enhancement (mm2)  0.006 [−0.01;0.16]  −0.017 [−0.06;0.01]  0.01  Maximal ESL        Baseline (mm2)  0.57 [0.14;1.07]  0.39 [0.13;1.14]  0.74  Follow-up (mm2)  1.01 [0.18;1.70]  0.43 [0.05;1.08]  0.11  Difference (mm2)  0.07 [−0.11;0.92]  −0.09 [−0.50;0.38]  0.11  Maximal ESL at frame level        Baseline (mm2)  0.46 [0.12;1.07]  0.38 [0.13;1.10]  0.72  Follow-up (mm2)  0.59 [0.14;1.45]  0.37 [0.04;1.04]  0.16  Difference (mm2)  0.02 [−0.16;0.47]  −0.09 [−0.50;0.33]  0.14  Mean lumen area (mm2)  8.1 ± 2.7  8.1 ± 3.1  0.97  Minimal lumen area (mm2)  6.1 ± 2.2  6.3 ± 2.7  0.64  Mean stent area (mm2)  8.8 ± 2.5  9.3 ± 3.1  0.39  Mean stent area late loss (mm2)  −0.3 ± 0.7  −0.1 ± 0.5  0.21  Minimal stent area (mm2)  7.1 ± 2.3  7.4 ± 2.7  0.49  Mean neointimal area (mm2)  1.0 ± 0.4  1.4 ± 0.5  0.0002  Neointima/stent area (%)  11.6 ± 4.7  15.8 ± 7.0  0.001  Stents with thrombus at follow-up (n)  7 (16%)  5 (12%)  0.76  Discussion The main findings of the SORT-OUT VII OCT study were as follows: (i) The pre-specified statistic test for non-inferiority showed that Orsiro did not exceed the limit for non-inferiority, but the distribution of data was non-normal and most optimal transformation applied post-hoc showed that it could not be excluded that Orsiro exceeded the limit for non-inferiority, (ii) testing for superiority, Orsiro showed significantly larger mean ESL at 13-month follow-up than Nobori, (iii) Orsiro DES had significantly larger increase in mean ESL from baseline to follow-up than Nobori DES, and the difference persisted in sensitivity analysis excluding the worst, most aneurysmatic cases in the Orsiro group, (iv) Nobori DES had a significantly larger mean neointima area and larger mean lumen area late loss, (v) strut coverage was complete or almost complete in the vast majority of patients but in both groups some stents still had coverage below 90% at 13-month follow-up, and (vi) all other healing parameters did not differ between the two stents. The finding in the main SORT-OUT VII study of similar 1-year clinical outcome after Orsiro and Nobori DES treatment except that more patients had ST in the Nobori group11 could indicate that the increased ESL in Orsiro either is not causing clinical events or the patients have been protected from ST by DAPT the first 12 months. An extended follow-up time is required to determine the associated risk when DAPT is discontinued. Still, the overall slightly more heterogeneous healing pattern in Nobori treated vessels might increase the risk of clinical events more than increased ESL as reflected in the difference in 1-year ST. Aneurysms and extra stent lumen Angiographic detected coronary aneurysms after DES implantation are infrequent findings with an incidence of 0.3 to 6.0%.13,14 Aneurysms are defined as localized angiographic dilatation of a segment of the coronary artery more than 50% larger than the adjacent reference vessel.15 Angiographic dilation <50% of the reference vessel at the site of a stent with contrast staining outside is known as peri-stent contrast staining (PSS).15 PSS corresponds to a segment of OCT-detected ESL or evagination.16 Both angiographic aneurysms, PSS and larger OCT-detected ESL have been associated with increased risk of ST.13,15–17 A previous study evaluating the occurrence of OCT-detected ESL in different DESs reported that ESL was related to treatment by the first generation sirolimus-eluting stent (Cypher Select) and was almost completely absent in newer generation DES.17 The present study challenges these findings as major aneurysms were formed in the Orsiro group during follow-up (Figure 5) and a number of minor aneurysms or clearly explicable evaginations were found in both groups. It cannot be excluded that formation of larger aneurysms could be due to injury to the vessel wall and thus not related to any specific stent type. Nevertheless, the increased ESL from baseline to follow-up in Orsiro treated patients was significant despite excluding the cases with large aneurysms from the analysis. The polymer degradation time for the Orsiro DES is 1–2 years and 6–9 months for the Nobori DES. The increase in ESL at 13 months in the Orsiro group compared with the Nobori group might be a result of a transient reaction towards the polymer at the 13-month time point. Radu et al. defined OCT-detected evaginations as an outward bulge in the luminal vessel between apposed struts with a maximum depth exceeding that of the actual strut thickness.17 Using this definition almost all patients in both treatment groups had evaginations limiting the potential value of this variable as an indicator of patients at increased risk for ST. Awaiting longer term clinical follow-up, the clinically most relevant variables for lumen outside the stent are likely related to the total lumen outside the stent and the size of individual evaginations/aneurysms exceeding threshold where the flow disturbance in the vessel bulge is substantial. Figure 5 View largeDownload slide OCT aneurysm—OCT images from the three large aneurysm found in the study population.—A Pre-existing aneurysm in a Nobori DES treated patient with size reduction at 13-month follow-up. B, C Induced aneurysms in segments treated by Orsiro DES. D OCT longitudinal-view. Yellow box indicates the aneurysm shown in B. Note the multiple smaller aneurysms in the stented segment indicating a more generalized response. E Follow-up angiography after 13 months. White box indicates the aneurysm. Figure 5 View largeDownload slide OCT aneurysm—OCT images from the three large aneurysm found in the study population.—A Pre-existing aneurysm in a Nobori DES treated patient with size reduction at 13-month follow-up. B, C Induced aneurysms in segments treated by Orsiro DES. D OCT longitudinal-view. Yellow box indicates the aneurysm shown in B. Note the multiple smaller aneurysms in the stented segment indicating a more generalized response. E Follow-up angiography after 13 months. White box indicates the aneurysm. Coverage and degree of neointima Incomplete neointimal coverage is a predictor of late ST. A ratio of uncovered to all struts exceeding 30% in 2–3 mm long in-stent sections was found in a histopathological study to be associated with ST.4 Both stent groups in this study showed on average a high degree of coverage after 13-month but with an uneven distribution, and an unsettling fraction of patients in both arms had more than 10% uncovered struts (Figure 4A). The magnitude of clinical risk by OCT detected incomplete strut coverage is unknown and should likely be evaluated in combination with other healing variables. The LEADERS OCT sub-study found only 0.6% uncovered struts for BES after 9 months.18 Recently the HATTRICK-OCT trial studying the Orsiro DES in non-diabetic patients with acute coronary syndrome found only 3.9% uncovered struts after 3 months19 and a study of Orsiro DES in patients with STEMI, eligible for a two-step procedure, demonstrated coverage of 98.7% after 90 days.20 For the Nobori DES, a similar level of coverage has recently been reported (in 17 patients, frequency of uncovered struts at 12-month: 1.55 ± 1.63%).21 Direct inter-study comparison of coverage rates should be performed with caution as differences in implantation techniques, degree of lesion coverage, and fraction of patients with diabetes, could cause differences in the observed healing responses. Assuming an even distribution of neointimal tissue, an increased neointima area is related to the degree of strut coverage but excess hyperplasia is the main cause of in-stent restenosis22 and the related angiographic measure of lumen loss is a well-established predictor of in-stent restenosis and TLR.23,24 In Nobori DES, the mean neointima area, the minimal lumen late loss and the mean lumen area late loss were increased, but NIT (tissue thickness on struts) did not differ and together with the increased fraction of patients with less than 90% coverage in the Nobori arm, this may indicate a more heterogeneous healing pattern after Nobori stenting with incomplete healed sections and sections with excess neointima formation. Malapposition Stent strut malapposition is a frequent finding in patients presenting with ST25,26 and several mechanisms have been proposed to increase the risk of acquired malapposition, such as stent recoil, vessel relaxation, positive remodelling, and localized evaginations of the vessel wall due to hypersensitive reactions.17,27 At baseline, we observed no difference in percentages of malapposed struts, and both stents demonstrated ability to resolve baseline malapposition with no significant difference in number of persistent or abolished clusters at 13-month follow-up. The small number of patients with acquired malapposition in clusters precludes firm conclusions about the acquired malapposition. Yet, our findings suggest a reaction towards the dissolving polymer in the Orsiro group and resolving thrombus/vessel relaxation in the Nobori group. Stent area and recoil The stents were implanted with similar average balloon pressures in vessels with similar angiographic reference diameters. Still, a slightly smaller MSA in the Orsiro group was detected and might represent acute recoil. Late stent recoil was only found in lesions treated with the Nobori DES indicating that the thin strut Orsiro maintains sufficient radial strength over time and that the enhancement in ESL is not explained by late stent recoil. Clinical endpoints One-year clinical results in the main study, SORT OUT VII,11 indicated non-inferiority of the Orsiro when compared with the Nobori DES. TLF occurred in 3.8% and 4.6% for the Orsiro and the Nobori DES, respectively, with a significantly lower rate of ST in the Orsiro than the Nobori group. A slightly lower rate of clinical events were found in our substudy-population which might be due to selection of a lower risk group for the OCT substudy or an effect of optimization of the PCI implantation result in some patients based on procedural OCT findings. Clinical perspectives The safety in use of first generation DES was compromised by incomplete healing and development of peri-stent evaginations and aneurysms. It has been reported that such healing patterns are almost absent with newer generation of DES, but the findings in our study challenges this perception. Careful evaluation of clinical outcome after discontinuation of DAPT is required and the findings may indicate that careful evaluation of healing patterns before introduction and widespread use of new stents is still warranted. Study limitations An inherent limitation of most OCT studies on stent performance is the follow-up selection of healthy survivors due to a low rate of patients with clinical events investigated by OCT. The study was one of the largest randomized OCT-studies on stent performance with matched baseline and follow-up analysis. Yet, the sample size remains minor and the most severely diseased patients omitted, which tends to increase the risk of type 1 and 2 errors. Coverage was verified if struts were clearly covered, but with the axial resolution of OCT at 10–15 µm, thin layers of tissue coverages (<10 µm) are not readily identified.28 Conclusion Orsiro DES had a significantly larger increase in vessel lumen outside the stent (ESL) during follow-up than Nobori DES and it could not be ruled out if Orsiro DES exceeded the limit for non-inferiority in 13-month mean ESL. Nobori DES was associated with a healing pattern with more heterogeneous neointima distribution while stent strut coverage did not differ significantly between the two stents. Supplementary data Supplementary data are available at European Heart Journal—Cardiovascular Imaging online. Acknowledgements The authors wish to acknowledge project co-ordinator Helle Cappelen from Odense University Hospital, and Lars Peter Joergensen, Pia Stycke Ottosen, and Karin Moeller Pedersen as well as research secretary Helle Bargsteen, all from Aarhus University Hospital. Conflict of Interest: Dr. Holm has received institutional research grants from Biotronik, Terumo, Abbott, Boston Scientific, Medtronic, Biosensors, Reva Medical, Elixir, Medis medical imaging, Cordis, and St. Jude Medical, and speakers fee from St. Jude Medical, Terumo and Reva Medical. Dr. Lassen has received grants from Terumo, Biotronik, Boston Scientific, Biosensors, St. Jude medical and Abbott and honorarium from Biotronik, Biosensors and St Jude medical. Dr. Jensen has received research grants from Terumo, Biotronik, St Jude Medical, and Biosensors to her institution and honoraria from St Jude Medical and Biotronik. Dr. Christiansen reported institutional research grants from Biotronik, Terumo, Abbott, Boston Scientific, Biosensors, Elixir, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Funding The study was supported by institutional research grants from Biotronik and Terumo. References 1 Tada T, Byrne RA, Simunovic I, King LA, Cassese S, Joner M et al.   Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. JACC Cardiovasc Interv  2013; 6: 1267– 74. Google Scholar CrossRef Search ADS PubMed  2 Jensen LO, Maeng M, Kaltoft A, Thayssen P, Hansen HHT, Bottcher M et al.   Stent thrombosis, myocardial infarction, and death after drug-eluting and bare-metal stent coronary interventions. J Am Coll Cardiol  2007; 50: 463– 70. Google Scholar CrossRef Search ADS PubMed  3 Otsuka F, Nakano M, Ladich E, Kolodgie FD, Virmani R. Pathologic etiologies of late and very late stent thrombosis following first-generation drug-eluting stent placement. Thrombosis  2012; 2012: 608593. Google Scholar CrossRef Search ADS PubMed  4 Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC et al.   Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation  2007; 115: 2435– 41. Google Scholar CrossRef Search ADS PubMed  5 Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E et al.   Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol  2006; 48: 193– 202. Google Scholar CrossRef Search ADS PubMed  6 Jensen LO, Thayssen P, Christiansen EH, Maeng M, Ravkilde J, Hansen KN et al.   Safety and efficacy of everolimus- versus sirolimus-eluting stents: 5-year results from SORT OUT IV. J Am Coll Cardiol  2016; 67: 751– 62. Google Scholar CrossRef Search ADS PubMed  7 Kereiakes DJ, Meredith IT, Windecker S, Lee Jobe R, Mehta SR, Sarembock IJ et al.   Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial. Circ Cardiovasc Interv  2015; 8: e002372. Google Scholar CrossRef Search ADS PubMed  8 Otsuka F, Cheng Q, Yahagi K, Acampado E, Sheehy A, Yazdani SK et al.   Acute thrombogenicity of a durable polymer everolimus-eluting stent relative to contemporary drug-eluting stents with biodegradable polymer coatings assessed ex vivo in a swine shunt model. JACC Cardiovasc Interv  2015; 8: 1248– 60. Google Scholar CrossRef Search ADS PubMed  9 Biotronik - Product details - Orsiro http://biotronik.cdn.mediamid.com/cdn_bio_doc/bio24299/18380/bio24299.pdf (26 February 2017, date last accessed). 10 Terumo. Nobori® - Drug eluting stent. http://www.terumo-europe.com/en-emea/interventional-cardiology/stents/drug-eluting-stent/nobori%C2%AE-drug-eluting-stent (April 2016, date last accessed). 11 Jensen LO, Thayssen P, Maeng M, Ravkilde J, Krusell LR, Raungaard B et al.   Randomized comparison of a biodegradable polymer ultrathin strut sirolimus-eluting stent with a biodegradable polymer biolimus-eluting stent in patients treated with percutaneous coronary intervention: the SORT OUT VII trial. Circ Cardiovasc Interv  2016; 9: e003610. Google Scholar CrossRef Search ADS PubMed  12 Kim BK, Shin DH, Kim JS, Ko YG, Choi D, Jang Y et al.   Optical coherence tomography-based evaluation of malapposed strut coverage after drug-eluting stent implantation. Int J Cardiovasc Imaging  2012; 28: 1887– 94. Google Scholar CrossRef Search ADS PubMed  13 Alfonso F, Perez-Vizcayno MJ, Ruiz M, Suarez A, Cazares M, Hernandez R et al.   Coronary aneurysms after drug-eluting stent implantation: clinical, angiographic, and intravascular ultrasound findings. J Am Coll Cardiol  2009; 53: 2053– 60. Google Scholar CrossRef Search ADS PubMed  14 Aoki J, Kirtane A, Leon MB, Dangas G. Coronary artery aneurysms after drug-eluting stent implantation. JACC Cardiovasc Interv  2008; 1: 14– 21. Google Scholar CrossRef Search ADS PubMed  15 Tada T, Kadota K, Hosogi S, Kubo S, Ozaki M, Yoshino M et al.   Optical coherence tomography findings in lesions after sirolimus-eluting stent implantation with peri-stent contrast staining. Circ Cardiovasc Interv  2012; 5: 649– 56. Google Scholar CrossRef Search ADS PubMed  16 Radu MD, Engstrom T. Casting light on coronary evaginations: different mechanisms in different coronary devices? Eur Heart J  2016; 37: 2050– 54. Google Scholar CrossRef Search ADS PubMed  17 Radu MD, Raber L, Kalesan B, Muramatsu T, Kelbaek H, Heo J et al.   Coronary evaginations are associated with positive vessel remodelling and are nearly absent following implantation of newer-generation drug-eluting stents: an optical coherence tomography and intravascular ultrasound study. Eur Heart J  2014; 35: 795– 807. Google Scholar CrossRef Search ADS PubMed  18 Barlis P, Regar E, Serruys PW, Dimopoulos K, van der Giessen WJ, van Geuns RJ et al.   An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: a LEADERS trial sub-study. Eur Heart J  2010; 31: 165– 76. Google Scholar CrossRef Search ADS PubMed  19 Karjalainen PP, Varho V, Nammas W, Mikkelsson J, Pietila M, Ylitalo A et al.   Early neointimal coverage and vasodilator response following biodegradable polymer sirolimus-eluting vs. durable polymer zotarolimus-eluting stents in patients with acute coronary syndrome -HATTRICK-OCT trial. Circ J  2015; 79: 360– 7. Google Scholar CrossRef Search ADS PubMed  20 Secco GG, Mattesini A, Fattori R, Parisi R, Castriota F, Vercellino M et al.   Time-related changes in neointimal tissue coverage of a novel Sirolimus eluting stent: serial observations with optical coherence tomography. Cardiovasc Revasc Med  2016; 17: 38– 43. Google Scholar CrossRef Search ADS PubMed  21 Konishi A, Shinke T, Otake H, Takaya T, Osue T, Kinutani H et al.   Serial optical coherence tomography evaluation at 6, 12, and 24 months after biolimus A9-eluting biodegradable polymer-coated stent implantation. Can J Cardiol  2015; 31: 980– 8. Google Scholar CrossRef Search ADS PubMed  22 Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA et al.   Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. A serial intravascular ultrasound study. Circulation  1997; 95: 1366– 9. Google Scholar CrossRef Search ADS PubMed  23 Pocock SJ, Lansky AJ, Mehran R, Popma JJ, Fahy MP, Na Y et al.   Angiographic surrogate end points in drug-eluting stent trials: a systematic evaluation based on individual patient data from 11 randomized, controlled trials. J Am Coll Cardiol  51: 23– 32. CrossRef Search ADS PubMed  24 Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary restenosis for drug-eluting stent comparison. Circulation  2005; 111: 3435– 42. Google Scholar CrossRef Search ADS PubMed  25 Foin N, Gutierrez-Chico JL, Nakatani S, Torii R, Bourantas CV, Sen S et al.   Incomplete stent apposition causes high shear flow disturbances and delay in neointimal coverage as a function of strut to wall detachment distance: implications for the management of incomplete stent apposition. Circ Cardiovasc Interv  2014; 7: 180– 9. Google Scholar CrossRef Search ADS PubMed  26 Taniwaki M, Radu MD, Zaugg S, Amabile N, Garcia-Garcia HM, Yamaji K et al.   Mechanisms of very late drug-eluting stent thrombosis assessed by optical coherence tomography. Circulation  2016; 133: 650– 60. Google Scholar CrossRef Search ADS PubMed  27 Nakatani S, Onuma Y, Ishibashi Y, Karanasos A, Regar E, Garcia-Garcia HM et al.   Incidence and potential mechanism of resolved, persistent and newly acquired malapposition three days after implantation of self-expanding or balloon-expandable stents in a STEMI population: insights from optical coherence tomography in the APPOSITION II study. EuroIntervention  2015; 11: 885– 94. Google Scholar CrossRef Search ADS PubMed  28 Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG et al.   Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol  2012; 59: 1058– 72. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. 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Abstract

Abstract Aims To show non-inferiority of the 67- or 87 µm thick, sirolimus-eluting Orsiro drug eluting stent (DES) to the 122 µm thick, biolimus-eluting Nobori DES regarding size of vessel lumen outside the stent at 13-month follow-up. Methods and results This study was a substudy to the SORT-OUT VII trial, a prospective, 1:1-randomized, comparison of the two stents in patients with stable coronary artery disease or acute coronary syndrome. Optical coherence tomography was acquired after percutaneous coronary intervention and at 13-month follow-up. The substudy was powered to access non-inferiority (Δ = 0.60 mm2) of the Orsiro DES to the Nobori DES for the primary endpoint of mean extra stent lumen (ESL) i.e. vessel lumen outside the stent at 13-month follow-up. We randomized 124 patients to Orsiro (n = 60) or Nobori (n = 64). Due to a difference in the one-sided 95%-confidence interval of 0.26 mm2, but increased to 0.82 mm2 after appropriate log-transformation, it could not be rejected that Orsiro exceeded the non-inferiority limit. Testing for superiority, Orsiro had a significantly larger mean ESL at follow-up (Orsiro: 0.11 mm2 [0.02;0.30] mm2, Nobori: 0.03 mm2 [0.00;0.17] mm2, P = 0.04). Stent strut coverage was, Orsiro: 97.6 % [93.8;99.4]%, and Nobori: 96.3 % [90.5;98,6]% (P = 0.13). Conclusion Orsiro DES had a significantly larger mean ESL at follow-up and it could not be excluded that Orsiro exceeded the limit for non-inferiority. Nobori DES had a more heterogeneous distribution of neointima but stent strut coverage did not differ significantly between the two stents. drug-eluting stents , bioresorbable polymer stents , optical coherence tomography Introduction First generation coronary drug eluting stents (DES) with permanent polymers are associated with increased risk of late- and very late stent thrombosis (ST) when compared with bare metal stents (BMS).1,2 Underlying pathologic mechanisms include hypersensitivity reactions towards the polymer, resulting in delayed vessel healing with incomplete neointimal coverage and aneurysmatic changes of the vessel wall.3–5 Newer generation DES designed with biocompatible polymers improved the DES safety profile,6 and latest generation DES with thinner stent platforms and biodegradable polymers were aimed to improve early healing and reduce the risk of adverse long-term reactions.7 Differences in stent platforms, biocompatibility, and degradation pace of polymers may influence healing patterns.8 The purpose of this study was to compare 13-month stent performance and vessel wall healing response, evaluated by optical coherence tomography (OCT), after implantation of the 67–87 µm thick, sirolimus-eluting Orsiro DES (Biotronik, Germany), and a 122 µm thick biolimus-eluting Nobori DES (Terumo, Jp) in patients with stable angina pectoris (SAP) or acute coronary syndrome (ACS). Methods Study design The SORT-OUT VII OCT study was a substudy to the clinical SORT-OUT VII trial (NCT01879358), a prospective, randomized, multi-centre, all-comer trial, enrolling 2525 patients. The substudy was conducted at Odense University Hospital and Aarhus University Hospital, Denmark. The OCT substudy was notified after first enrollment in the main SORT-OUT VII study. Randomization was stratified by gender and diabetes, and participation in the OCT substudy. Patients eligible for the substudy were included with a planned target of 120 patients. Patients were randomized 1:1 to receive either sirolimus-eluting Orsiro DES (BiotronikTM, Berlin, Germany) or biolimus-eluting Nobori DES (Terumo CorporationTM, Tokyo, Japan). Randomization was stratified by sex and diabetes, and participation in the OCT substudy. OCT was performed immediately after percutaneous coronary intervention (PCI) and at 13-month follow-up. The study included patients aged ≥ 18 years with stable—or unstable coronary artery disease, ST-segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI), and at least one coronary lesion with more than 50% diameter stenosis. Exclusion criteria for this substudy were aorto-ostial lesions, s-creatinine > 120µmol/L, severely tortuous target coronary artery, life expectancy less than 1 year, allergy to aspirin, clopidogrel, ticagrelor, prasugrel, sirolimus, or biolimus. The main SORT-OUT VII trial and the SORT-OUT VII OCT substudy were approved by The Central Denmark Region Committees on Health Research Ethics. All patients provided written informed consent for participation in the trial (NCT01879358). Study stents The CE-certified Orsiro DES is designed with a permanent thin ‘ProBIO’ coating aimed at reducing ion-release, and a poly-l-lactic acid biodegradable polymer eluting sirolimus during the first 12–14 weeks. The polymer is almost completely degraded within 1–2 years. The stent features two different platform designs; a small size (diameters 2.25 to 3.0 mm, strut thickness 60  + 7 µm polymer) and a larger size (diameters 3.5 to 4.0 mm, strut thickness 80 + 7 µm polymer).9 The CE-certified Nobori DES is based on a stainless steel platform with a thin permanent parylene coating, and a biodegradable polymer coating of the abluminal side of struts. The polymer elutes biolimus A9 (Biosensors International, Singapore) for the first approximately 30 days during the polymer degradation lasting 6–9 months. Strut thickness is 112 + 10 μm polymer.10 Study procedure Medical treatment and PCI was performed according to standard procedures as previously described.11 Use of pre-dilatation of the lesion, direct stenting or post-dilatation of the stent was decided by the PCI-operator, OCT could be used for evaluating the procedure at the discretion of the operator, and the baseline OCT-recording was performed as the final intervention before removing the guide wire. OCT acquisition OCT imaging was performed using the St. Jude Medical OCT-system (Illumien™ or Illumien OPTISTM) and a C7 Dragonfly™ catheter (St. Jude Medical, Minnesota, MN, USA) after intracoronary administration of nitroglycerine. OCT images were recorded at either 100 frames per second (fps) with a catheter pullback speed of 20 mm/s, or 180 fps with pullback speed 18 or 36 mm/s during flushing with contrast. Clinical follow-up and endpoints Clinical endpoints included all-cause mortality, cardiac death, myocardial infarction (MI), ST, and target lesion revascularization (TLR). The endpoints were obtained from health registries covering from discharge until 13-month angiography. Additional clinical endpoint definitions were described in the SORT-OUT VII main study.11 OCT analysis OCT acquired post-PCI and at 13-month follow-up were matched at frame-level and analysed by blinded observers using off-line semi-automated analysis software (QCU-CMS Research, Leiden, The Netherlands). The entire stent segment, including the margins 5 mm proximal and distal to the stent, were evaluated in all consecutive frames for recording quality, plaque type and extend, and thrombus. Thrombus was defined as an irregular mass appearing in the lumen with or without attachment to the vessel wall (Figure 1C). Quantitative OCT analysis was performed at 0.5 or 0.6 mm intervals after calibration of the OCT recordings. Lumen and stent contours, and areas were measured. At follow-up, tissue coverage was evaluated visually for each strut and neointimal thickness (NIT) was measured as the shortest distance from the centre of the strut blooming signal to the lumen border (Figure 1D). Struts were considered malapposed when the smallest distance from the centre of the leading strut blooming signal to the lumen contour exceeded the sum of the strut thickness + polymer + 20 µm (Figure 1F). Clusters of malapposed struts were defined as 10 counts of malapposed struts within five or less consecutive frames. At follow-up, clusters were classified into persistent, abolished or acquired. Figure 1 View largeDownload slide Endpoint illustration—A Extra stent lumen (ESL): lumen area outside stent, indicated by the red area. B Maximum ESL: the largest total area outside the stent in one frame. B1: Maximum ESL at frame level: area outside stent limited by two apposed struts, indicated by the yellow delineated area. C Thrombus: irregular mass appearing in the lumen. D Neointimal thickness (NIT): shortest distance from the centre of the strut to the lumen boarder. E Coverage: verified visible tissue on struts. F Malapposed strut. Clusters of malapposed struts defined as 10 counts of malapposed struts within five or less consecutive frames. Figure 1 View largeDownload slide Endpoint illustration—A Extra stent lumen (ESL): lumen area outside stent, indicated by the red area. B Maximum ESL: the largest total area outside the stent in one frame. B1: Maximum ESL at frame level: area outside stent limited by two apposed struts, indicated by the yellow delineated area. C Thrombus: irregular mass appearing in the lumen. D Neointimal thickness (NIT): shortest distance from the centre of the strut to the lumen boarder. E Coverage: verified visible tissue on struts. F Malapposed strut. Clusters of malapposed struts defined as 10 counts of malapposed struts within five or less consecutive frames. Primary and secondary endpoints (OCT) The primary endpoint of mean extra stent lumen (ESL) was evaluated by OCT at 13-month follow-up. ESL was defined as lumen area outside the stent contour (Figure 1A). Secondary endpoints included change in mean ESL from baseline to follow-up. Maximum ESL was measured and defined as the largest total area outside stent in one frame (Figure 1B). Maximum ESL at frame level was defined as the maximal area outside stent limited by two apposed struts (Figure 1B, B1). Additional secondary endpoints were malapposition at baseline and at 13-month follow-up, persistent-, abolished-, or acquired malapposed clusters, stent area late loss (late recoil), minimal lumen area (MLA), neointimal thickness (NIT), thrombus on stent struts at baseline, in-stent thrombus at follow-up and mean neointimal area calculated and measured as the area delineated abluminal by the stent contour and luminal by the lumen contour. Sample size Experience by treatment with the sirolimus eluting Cypher stent has demonstrated that evaginations and aneurysm formation are reflected in an increased maximum ESL of 0.60 ± 0.83 mm2 at a mean 1-year follow-up.12 The mean ESL area was estimated to be 0.30 mm2 and a non-inferiority margin of 0.60 mm2 was decided as the clinically acceptable difference. With an assumed standard deviation of 1.0 mm2 and a power of 90% the estimated numbers of patients required were 96 patients. By including 120 patients 20% could be lost to follow-up. Statistics Continuous variables are presented as mean ± standard deviation if following a Gaussian distribution or alternatively as median and inter-quartile range. Non-parametric data are presented as absolute numbers and percentages. Differences in characteristics between the two DES were compared using Student’s t-test or Mann–Whitney test as appropriate. χ2 test was used for comparing categorical variables, alternative Fisher’s exact test in case of cell values less than 5. Due to a non-normal distribution of the primary endpoint data of mean ESL at 13-month, several transformations were made to find the most appropriate transformation (log (ESL + 0.001)). Median values and confidence intervals (CI) of the transformed analysis were back transformed and compared with the preplanned analysis to evaluate if non-inferiority of Orsiro DES to Nobori DES was met. Statistical significance was accepted for P-values < 0.05. All statistical analyses were performed using STATA version 13 (STATA Inc., College Station, TX). Results We included 124 randomized patients in the OCT substudy between June 2013 and February 2014. Sixty patients were treated with the Orsiro DES, while 64 patients were treated with the Nobori DES. Clinical follow-up at 13-month was available in all patients. Baseline characteristics were well balanced between the two groups, except for treatment indication, which varied between stable- and unstable angina pectoris between the two groups (Table 1). All patients received the allocated study stent. Almost 15% of the patients in both groups had diabetes. The most frequently treated vessel in both groups was LAD (Orsiro: 55%, Nobori: 50%, P = 0.52) (Table 2). Table 1 Baseline characteristics   Orsiro DES  Nobori DES  P-value  No. of patients  60  64    Age (year)  61 ± 9.3  60 ± 10.4  0.81  Male gender  50 (83%)  52 (81%)  0.76  Diabetes  9 (15%)  10 (16%)  0.93  Systolic blood pressure (mmHg)  142 ± 20  138 ± 22  0.29  Diastolic blood pressure (mmHg)  79 ± 11  78 ± 12  0.72  Hypertension treatment  25 (42%)  27 (42%)  0.95  Current smoker  19 (32%)  20 (33%)  0.90  Ischaemic heart disease in family  33 (59%)  30 (49%)  0.29  Statin treatment  37 (62%)  34 (53%)  0.34  Previous CABG  1 (2%)  2 (3%)  1.00  Previous PCI  11 (18%)  6 (9%)  0.15  Previous AMI  9 (15%)  5 (8%)  0.21  Previous heart operation  1 (2%)  2 (3%)  1.00  BMI (kg/m2)  27.9 ± 4.9  26.9 ± 4.1  0.22  Indication      0.04  Stable angina pectoris  27 (45%)  38 (59%)    Unstable angina pectoris  9 (15%)  1 (2%)    NSTEMI  15 (25%)  14 (22%)    STEMI  9 (15%)  11 (17%)    Baseline OCT characteristics  No. of patients  45  43  88  Mean lumen area (mm2)  8.1 ± 2.3  8.8 ± 3.0  0.22  Mean stent area (mm2)  8.5 ± 2.3  9.2 ± 3.0  0.23  Thrombus on struts, per patient level (n)  31 (69%)  27 (63%)  0.65    Orsiro DES  Nobori DES  P-value  No. of patients  60  64    Age (year)  61 ± 9.3  60 ± 10.4  0.81  Male gender  50 (83%)  52 (81%)  0.76  Diabetes  9 (15%)  10 (16%)  0.93  Systolic blood pressure (mmHg)  142 ± 20  138 ± 22  0.29  Diastolic blood pressure (mmHg)  79 ± 11  78 ± 12  0.72  Hypertension treatment  25 (42%)  27 (42%)  0.95  Current smoker  19 (32%)  20 (33%)  0.90  Ischaemic heart disease in family  33 (59%)  30 (49%)  0.29  Statin treatment  37 (62%)  34 (53%)  0.34  Previous CABG  1 (2%)  2 (3%)  1.00  Previous PCI  11 (18%)  6 (9%)  0.15  Previous AMI  9 (15%)  5 (8%)  0.21  Previous heart operation  1 (2%)  2 (3%)  1.00  BMI (kg/m2)  27.9 ± 4.9  26.9 ± 4.1  0.22  Indication      0.04  Stable angina pectoris  27 (45%)  38 (59%)    Unstable angina pectoris  9 (15%)  1 (2%)    NSTEMI  15 (25%)  14 (22%)    STEMI  9 (15%)  11 (17%)    Baseline OCT characteristics  No. of patients  45  43  88  Mean lumen area (mm2)  8.1 ± 2.3  8.8 ± 3.0  0.22  Mean stent area (mm2)  8.5 ± 2.3  9.2 ± 3.0  0.23  Thrombus on struts, per patient level (n)  31 (69%)  27 (63%)  0.65  Table 2 Procedural characteristics   Orsiro DES  Nobori DES  P-value  N  60  64    Number of stents  1.1 ± 0.4  1.3 ± 0.7  0.08  Nominal stent length (mm)  20.5 ± 7.6  24.4 ± 12.9  0.18  Lesions length (mm)  16.0 ± 6.9  18.1 ± 9.6  0.47  Max. balloon diameter (mm)  3.6 ± 0.5  3.5 ± 0.5  0.91  Max. balloon pressure (mmHg)  16.1 ± 3.5  16.5 ± 3.7  0.50  Reference diameter (visual estimate) (mm)  3.5 ± 0.5  3.4 ± 0.5  0.73  Reference diameter(combined OCT and QCA) (mm)  3.6 ± 0.6  3.6 ± 0.7  0.76  Treated vessel        RCA  18 (30%)  21 (33%)  0.56  LAD  33 (55%)  32 (50%)  0.52  LCA  9 (15%)  11 (17%)  0.56    Orsiro DES  Nobori DES  P-value  N  60  64    Number of stents  1.1 ± 0.4  1.3 ± 0.7  0.08  Nominal stent length (mm)  20.5 ± 7.6  24.4 ± 12.9  0.18  Lesions length (mm)  16.0 ± 6.9  18.1 ± 9.6  0.47  Max. balloon diameter (mm)  3.6 ± 0.5  3.5 ± 0.5  0.91  Max. balloon pressure (mmHg)  16.1 ± 3.5  16.5 ± 3.7  0.50  Reference diameter (visual estimate) (mm)  3.5 ± 0.5  3.4 ± 0.5  0.73  Reference diameter(combined OCT and QCA) (mm)  3.6 ± 0.6  3.6 ± 0.7  0.76  Treated vessel        RCA  18 (30%)  21 (33%)  0.56  LAD  33 (55%)  32 (50%)  0.52  LCA  9 (15%)  11 (17%)  0.56  Clinical results At 13-month clinical follow-up, NSTEMI occurred in one of 60 patients in the Orsiro group and one of 64 patients in the Nobori group. No patients had stent thrombosis. One patient treated with a Nobori DES suffered non-cardiac death. OCT 13-month follow-up results OCT follow-up was available in 88 patients (Figure 2). The primary outcome measure of difference in mean ESL at 13-month between the two stent groups was mean 0.12 mm2 with a one-sided 95%-CI of 0.26 mm2. Result after appropriate log-transformation yielded a one-sided 95%-CI up to 0.82 mm2. With this difference in CI, we could not reject that Orsiro exceeded the non-inferiority limit (0.60 mm2): see Figure 3B. Testing for superiority, the median ESL at 13-month follow-up was 0.11 mm2 [0.02;0.30] mm2 for the Orsiro DES and 0.03 mm2 [0.00;0.17] mm2 for the Nobori DES (P = 0.04) (Figure 3A). Orsiro DES showed a significant larger increase in mean ESL from baseline to 13-month compared with the Nobori DES (0.006 mm2 [−0.012;0.160] mm2 vs. −0.017mm2 [−0.060;0.012] mm2, P = 0.01) (Figure 3C). The significant difference in favour of Nobori DES was confirmed by sensitivity analysis excluding two cases in the Orsiro arm with large aneurysms (Figures 3A, 5B and C). Figure 2 View largeDownload slide Patient flow chart—AMI, acute myocardial infarction; DES, drug eluting stent; FU, follow-up; OCT, optical coherence tomography. Figure 2 View largeDownload slide Patient flow chart—AMI, acute myocardial infarction; DES, drug eluting stent; FU, follow-up; OCT, optical coherence tomography. Figure 3 View largeDownload slide Endpoint plots—A Primary endpoint of mean extra stent lumen (ESL) at 13-month follow-up. B 95%-Confidence interval (CI) for non-transformed data and log (ESL + 0.001) transformed data showing difference in non-inferiority margin. C Baseline corrected mean ESL. The significant difference in favour of Nobori DES was confirmed by sensitivity analysis excluding two cases with mayor aneurysms in the Orsiro arm. D Difference in malapposition vs. difference in mean ESL. Red box indicate patients with a decrease in amount of mallapposed struts but an increase in mean ESL. Figure 3 View largeDownload slide Endpoint plots—A Primary endpoint of mean extra stent lumen (ESL) at 13-month follow-up. B 95%-Confidence interval (CI) for non-transformed data and log (ESL + 0.001) transformed data showing difference in non-inferiority margin. C Baseline corrected mean ESL. The significant difference in favour of Nobori DES was confirmed by sensitivity analysis excluding two cases with mayor aneurysms in the Orsiro arm. D Difference in malapposition vs. difference in mean ESL. Red box indicate patients with a decrease in amount of mallapposed struts but an increase in mean ESL. Coverages and neointimal thickness NIT The median percentage of covered struts was similar in the two groups (97.6% [93.8;99.4] % (Orsiro DES), 96.3% [90.5;98.69] % (Nobori DES), (P = 0.13)). A total of 6 patients (13%) in the Orsiro treated group and 9 patients (21%) treated with a Nobori DES showed coverage levels below 90% after 13-month (Figure 4A). The median NIT was 70.8 µm [62.8;96.7] µm in the Orsiro group and 74.6 µm [62.9;114.8] µm in the Nobori group (P = 0.43). The median neointimal area was significant larger for the Nobori DES (1.28 mm2 [0.96;1.68] mm2 vs. Orsiro: 0.92 mm2 [0.70;1.13] mm2, P = 0.0001) (Figure 4B and C). Figure 4 View largeDownload slide Secondary endpoints—A Stent strut coverage. Coverage below 90% was found in 13% in the Orsiro group vs. 21% in the Nobori group. B Mean neointimal thickness (NIT). No siginifcant difference between the two DESs. C Mean neointimal area. Significant larger area for the Nobori DES (1.28 mm2) than for the Orsiro DES (0.92 mm2) (P = 0.001). Figure 4 View largeDownload slide Secondary endpoints—A Stent strut coverage. Coverage below 90% was found in 13% in the Orsiro group vs. 21% in the Nobori group. B Mean neointimal thickness (NIT). No siginifcant difference between the two DESs. C Mean neointimal area. Significant larger area for the Nobori DES (1.28 mm2) than for the Orsiro DES (0.92 mm2) (P = 0.001). Malapposition At baseline, malapposed struts were found in 2.9% [0.4;10.0] % and 2.1% [0.7;6.8] % of analysed struts in the Orsiro, and the Nobori DES respectively (P = 0.66). At 13-month follow-up, malapposition was 0.0% [0.0;1.1] % (Orsiro DES) and 0.0% [0.0;0.5] % (Nobori DES), (P = 0.37). We found no difference in number of patients with clustered baseline malapposition; 24 patients with a total of 37 clusters in the Orsiro group compared with 19 patients with a total of 30 clusters in the Nobori group (P = 0.39). Clusters of acquired malapposition at follow-up were found in four patients (9%) in the Orsiro group and two patients (5%) in the Nobori group (P = 0.68). Number of patients having clusters of persistent or resolved of malapposed clusters did not differ between the stents (Orsiro: 6 patients (13%), Nobori: 2 patients (5%), P = 0.27 and Orsiro: 20 patients (44%), Nobori: 18 patients (42%), P = 0.81, respectively (Supplementary data online, Table S1). Lumen size and stent properties Baseline minimal lumen area (MLA) was 6.55 mm2 (Orsiro) and 7.07 mm2 (Nobori) (P = 0.28), while minimal stent area (MSA) was 7.04 mm2 (Orsiro) and 7.62 mm2 (Nobori) (P = 0.26). Additional baseline properties are shown in Table 1. Mean lumen area late loss was significantly larger in the Nobori than in the Orsiro group (Nobori: 0.74  ± 0.82 mm2, Orsiro: 0.07 ± 1.06 mm2, P = 0.001), while MLA late loss did not differ statistically significantly (0.75  ± 1.06 mm2 vs. 0.47 ± 1.16 mm2, P = 0.25). Late stent recoil was only identified for Nobori (0.19 ± 0.85 mm2. Orsiro: −0.12 ± 0.89 mm2). Additional secondary endpoint results are shown in Table 3. Table 3 Primary and secondary endpoints   Orsiro DES  Nobori DES  P-value  Extra stent lumen area at 13 month follow-up (mm2)  0.11 [0.02;0.30]  0.03 [0.00;0.17]  0.04  Extra stent lumen area at baseline (mm2)  0.05 [0.01;0.13]  0.04 [0.02;0.14]  0.81  Extra stent lumen area enhancement (mm2)  0.006 [−0.01;0.16]  −0.017 [−0.06;0.01]  0.01  Maximal ESL        Baseline (mm2)  0.57 [0.14;1.07]  0.39 [0.13;1.14]  0.74  Follow-up (mm2)  1.01 [0.18;1.70]  0.43 [0.05;1.08]  0.11  Difference (mm2)  0.07 [−0.11;0.92]  −0.09 [−0.50;0.38]  0.11  Maximal ESL at frame level        Baseline (mm2)  0.46 [0.12;1.07]  0.38 [0.13;1.10]  0.72  Follow-up (mm2)  0.59 [0.14;1.45]  0.37 [0.04;1.04]  0.16  Difference (mm2)  0.02 [−0.16;0.47]  −0.09 [−0.50;0.33]  0.14  Mean lumen area (mm2)  8.1 ± 2.7  8.1 ± 3.1  0.97  Minimal lumen area (mm2)  6.1 ± 2.2  6.3 ± 2.7  0.64  Mean stent area (mm2)  8.8 ± 2.5  9.3 ± 3.1  0.39  Mean stent area late loss (mm2)  −0.3 ± 0.7  −0.1 ± 0.5  0.21  Minimal stent area (mm2)  7.1 ± 2.3  7.4 ± 2.7  0.49  Mean neointimal area (mm2)  1.0 ± 0.4  1.4 ± 0.5  0.0002  Neointima/stent area (%)  11.6 ± 4.7  15.8 ± 7.0  0.001  Stents with thrombus at follow-up (n)  7 (16%)  5 (12%)  0.76    Orsiro DES  Nobori DES  P-value  Extra stent lumen area at 13 month follow-up (mm2)  0.11 [0.02;0.30]  0.03 [0.00;0.17]  0.04  Extra stent lumen area at baseline (mm2)  0.05 [0.01;0.13]  0.04 [0.02;0.14]  0.81  Extra stent lumen area enhancement (mm2)  0.006 [−0.01;0.16]  −0.017 [−0.06;0.01]  0.01  Maximal ESL        Baseline (mm2)  0.57 [0.14;1.07]  0.39 [0.13;1.14]  0.74  Follow-up (mm2)  1.01 [0.18;1.70]  0.43 [0.05;1.08]  0.11  Difference (mm2)  0.07 [−0.11;0.92]  −0.09 [−0.50;0.38]  0.11  Maximal ESL at frame level        Baseline (mm2)  0.46 [0.12;1.07]  0.38 [0.13;1.10]  0.72  Follow-up (mm2)  0.59 [0.14;1.45]  0.37 [0.04;1.04]  0.16  Difference (mm2)  0.02 [−0.16;0.47]  −0.09 [−0.50;0.33]  0.14  Mean lumen area (mm2)  8.1 ± 2.7  8.1 ± 3.1  0.97  Minimal lumen area (mm2)  6.1 ± 2.2  6.3 ± 2.7  0.64  Mean stent area (mm2)  8.8 ± 2.5  9.3 ± 3.1  0.39  Mean stent area late loss (mm2)  −0.3 ± 0.7  −0.1 ± 0.5  0.21  Minimal stent area (mm2)  7.1 ± 2.3  7.4 ± 2.7  0.49  Mean neointimal area (mm2)  1.0 ± 0.4  1.4 ± 0.5  0.0002  Neointima/stent area (%)  11.6 ± 4.7  15.8 ± 7.0  0.001  Stents with thrombus at follow-up (n)  7 (16%)  5 (12%)  0.76  Discussion The main findings of the SORT-OUT VII OCT study were as follows: (i) The pre-specified statistic test for non-inferiority showed that Orsiro did not exceed the limit for non-inferiority, but the distribution of data was non-normal and most optimal transformation applied post-hoc showed that it could not be excluded that Orsiro exceeded the limit for non-inferiority, (ii) testing for superiority, Orsiro showed significantly larger mean ESL at 13-month follow-up than Nobori, (iii) Orsiro DES had significantly larger increase in mean ESL from baseline to follow-up than Nobori DES, and the difference persisted in sensitivity analysis excluding the worst, most aneurysmatic cases in the Orsiro group, (iv) Nobori DES had a significantly larger mean neointima area and larger mean lumen area late loss, (v) strut coverage was complete or almost complete in the vast majority of patients but in both groups some stents still had coverage below 90% at 13-month follow-up, and (vi) all other healing parameters did not differ between the two stents. The finding in the main SORT-OUT VII study of similar 1-year clinical outcome after Orsiro and Nobori DES treatment except that more patients had ST in the Nobori group11 could indicate that the increased ESL in Orsiro either is not causing clinical events or the patients have been protected from ST by DAPT the first 12 months. An extended follow-up time is required to determine the associated risk when DAPT is discontinued. Still, the overall slightly more heterogeneous healing pattern in Nobori treated vessels might increase the risk of clinical events more than increased ESL as reflected in the difference in 1-year ST. Aneurysms and extra stent lumen Angiographic detected coronary aneurysms after DES implantation are infrequent findings with an incidence of 0.3 to 6.0%.13,14 Aneurysms are defined as localized angiographic dilatation of a segment of the coronary artery more than 50% larger than the adjacent reference vessel.15 Angiographic dilation <50% of the reference vessel at the site of a stent with contrast staining outside is known as peri-stent contrast staining (PSS).15 PSS corresponds to a segment of OCT-detected ESL or evagination.16 Both angiographic aneurysms, PSS and larger OCT-detected ESL have been associated with increased risk of ST.13,15–17 A previous study evaluating the occurrence of OCT-detected ESL in different DESs reported that ESL was related to treatment by the first generation sirolimus-eluting stent (Cypher Select) and was almost completely absent in newer generation DES.17 The present study challenges these findings as major aneurysms were formed in the Orsiro group during follow-up (Figure 5) and a number of minor aneurysms or clearly explicable evaginations were found in both groups. It cannot be excluded that formation of larger aneurysms could be due to injury to the vessel wall and thus not related to any specific stent type. Nevertheless, the increased ESL from baseline to follow-up in Orsiro treated patients was significant despite excluding the cases with large aneurysms from the analysis. The polymer degradation time for the Orsiro DES is 1–2 years and 6–9 months for the Nobori DES. The increase in ESL at 13 months in the Orsiro group compared with the Nobori group might be a result of a transient reaction towards the polymer at the 13-month time point. Radu et al. defined OCT-detected evaginations as an outward bulge in the luminal vessel between apposed struts with a maximum depth exceeding that of the actual strut thickness.17 Using this definition almost all patients in both treatment groups had evaginations limiting the potential value of this variable as an indicator of patients at increased risk for ST. Awaiting longer term clinical follow-up, the clinically most relevant variables for lumen outside the stent are likely related to the total lumen outside the stent and the size of individual evaginations/aneurysms exceeding threshold where the flow disturbance in the vessel bulge is substantial. Figure 5 View largeDownload slide OCT aneurysm—OCT images from the three large aneurysm found in the study population.—A Pre-existing aneurysm in a Nobori DES treated patient with size reduction at 13-month follow-up. B, C Induced aneurysms in segments treated by Orsiro DES. D OCT longitudinal-view. Yellow box indicates the aneurysm shown in B. Note the multiple smaller aneurysms in the stented segment indicating a more generalized response. E Follow-up angiography after 13 months. White box indicates the aneurysm. Figure 5 View largeDownload slide OCT aneurysm—OCT images from the three large aneurysm found in the study population.—A Pre-existing aneurysm in a Nobori DES treated patient with size reduction at 13-month follow-up. B, C Induced aneurysms in segments treated by Orsiro DES. D OCT longitudinal-view. Yellow box indicates the aneurysm shown in B. Note the multiple smaller aneurysms in the stented segment indicating a more generalized response. E Follow-up angiography after 13 months. White box indicates the aneurysm. Coverage and degree of neointima Incomplete neointimal coverage is a predictor of late ST. A ratio of uncovered to all struts exceeding 30% in 2–3 mm long in-stent sections was found in a histopathological study to be associated with ST.4 Both stent groups in this study showed on average a high degree of coverage after 13-month but with an uneven distribution, and an unsettling fraction of patients in both arms had more than 10% uncovered struts (Figure 4A). The magnitude of clinical risk by OCT detected incomplete strut coverage is unknown and should likely be evaluated in combination with other healing variables. The LEADERS OCT sub-study found only 0.6% uncovered struts for BES after 9 months.18 Recently the HATTRICK-OCT trial studying the Orsiro DES in non-diabetic patients with acute coronary syndrome found only 3.9% uncovered struts after 3 months19 and a study of Orsiro DES in patients with STEMI, eligible for a two-step procedure, demonstrated coverage of 98.7% after 90 days.20 For the Nobori DES, a similar level of coverage has recently been reported (in 17 patients, frequency of uncovered struts at 12-month: 1.55 ± 1.63%).21 Direct inter-study comparison of coverage rates should be performed with caution as differences in implantation techniques, degree of lesion coverage, and fraction of patients with diabetes, could cause differences in the observed healing responses. Assuming an even distribution of neointimal tissue, an increased neointima area is related to the degree of strut coverage but excess hyperplasia is the main cause of in-stent restenosis22 and the related angiographic measure of lumen loss is a well-established predictor of in-stent restenosis and TLR.23,24 In Nobori DES, the mean neointima area, the minimal lumen late loss and the mean lumen area late loss were increased, but NIT (tissue thickness on struts) did not differ and together with the increased fraction of patients with less than 90% coverage in the Nobori arm, this may indicate a more heterogeneous healing pattern after Nobori stenting with incomplete healed sections and sections with excess neointima formation. Malapposition Stent strut malapposition is a frequent finding in patients presenting with ST25,26 and several mechanisms have been proposed to increase the risk of acquired malapposition, such as stent recoil, vessel relaxation, positive remodelling, and localized evaginations of the vessel wall due to hypersensitive reactions.17,27 At baseline, we observed no difference in percentages of malapposed struts, and both stents demonstrated ability to resolve baseline malapposition with no significant difference in number of persistent or abolished clusters at 13-month follow-up. The small number of patients with acquired malapposition in clusters precludes firm conclusions about the acquired malapposition. Yet, our findings suggest a reaction towards the dissolving polymer in the Orsiro group and resolving thrombus/vessel relaxation in the Nobori group. Stent area and recoil The stents were implanted with similar average balloon pressures in vessels with similar angiographic reference diameters. Still, a slightly smaller MSA in the Orsiro group was detected and might represent acute recoil. Late stent recoil was only found in lesions treated with the Nobori DES indicating that the thin strut Orsiro maintains sufficient radial strength over time and that the enhancement in ESL is not explained by late stent recoil. Clinical endpoints One-year clinical results in the main study, SORT OUT VII,11 indicated non-inferiority of the Orsiro when compared with the Nobori DES. TLF occurred in 3.8% and 4.6% for the Orsiro and the Nobori DES, respectively, with a significantly lower rate of ST in the Orsiro than the Nobori group. A slightly lower rate of clinical events were found in our substudy-population which might be due to selection of a lower risk group for the OCT substudy or an effect of optimization of the PCI implantation result in some patients based on procedural OCT findings. Clinical perspectives The safety in use of first generation DES was compromised by incomplete healing and development of peri-stent evaginations and aneurysms. It has been reported that such healing patterns are almost absent with newer generation of DES, but the findings in our study challenges this perception. Careful evaluation of clinical outcome after discontinuation of DAPT is required and the findings may indicate that careful evaluation of healing patterns before introduction and widespread use of new stents is still warranted. Study limitations An inherent limitation of most OCT studies on stent performance is the follow-up selection of healthy survivors due to a low rate of patients with clinical events investigated by OCT. The study was one of the largest randomized OCT-studies on stent performance with matched baseline and follow-up analysis. Yet, the sample size remains minor and the most severely diseased patients omitted, which tends to increase the risk of type 1 and 2 errors. Coverage was verified if struts were clearly covered, but with the axial resolution of OCT at 10–15 µm, thin layers of tissue coverages (<10 µm) are not readily identified.28 Conclusion Orsiro DES had a significantly larger increase in vessel lumen outside the stent (ESL) during follow-up than Nobori DES and it could not be ruled out if Orsiro DES exceeded the limit for non-inferiority in 13-month mean ESL. Nobori DES was associated with a healing pattern with more heterogeneous neointima distribution while stent strut coverage did not differ significantly between the two stents. Supplementary data Supplementary data are available at European Heart Journal—Cardiovascular Imaging online. Acknowledgements The authors wish to acknowledge project co-ordinator Helle Cappelen from Odense University Hospital, and Lars Peter Joergensen, Pia Stycke Ottosen, and Karin Moeller Pedersen as well as research secretary Helle Bargsteen, all from Aarhus University Hospital. Conflict of Interest: Dr. Holm has received institutional research grants from Biotronik, Terumo, Abbott, Boston Scientific, Medtronic, Biosensors, Reva Medical, Elixir, Medis medical imaging, Cordis, and St. Jude Medical, and speakers fee from St. Jude Medical, Terumo and Reva Medical. Dr. Lassen has received grants from Terumo, Biotronik, Boston Scientific, Biosensors, St. Jude medical and Abbott and honorarium from Biotronik, Biosensors and St Jude medical. Dr. Jensen has received research grants from Terumo, Biotronik, St Jude Medical, and Biosensors to her institution and honoraria from St Jude Medical and Biotronik. Dr. Christiansen reported institutional research grants from Biotronik, Terumo, Abbott, Boston Scientific, Biosensors, Elixir, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Funding The study was supported by institutional research grants from Biotronik and Terumo. References 1 Tada T, Byrne RA, Simunovic I, King LA, Cassese S, Joner M et al.   Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. JACC Cardiovasc Interv  2013; 6: 1267– 74. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Mar 1, 2018

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