=0 49), whereas the late luminal loss was larger in the Absorb group than in the Xience group (0 37 mm [0 45] vs 0 25 mm [0 25]; p non-inferiority

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1 Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, single-blind, multicentre clinical trial Patrick W Serruys, Bernard Chevalier, Yohei Sotomi, Angel Cequier, Didier Carrié, Jan J Piek, Ad J Van Boven, Marcello Dominici, Dariusz Dudek, Dougal McClean, Steffen Helqvist, Michael Haude, Sebastian Reith, Manuel de Sousa Almeida, Gianluca Campo, Andrés Iñiguez, Manel Sabaté, Stephan Windecker, Yoshinobu Onuma Summary Background No medium-term data are available on the random comparison between everolimus-eluting bioresorbable vascular scaffolds and everolimus-eluting metallic stents. The study aims to demonstrate two mechanistic properties of the bioresorbable scaffold: increase in luminal dimensions as a result of recovered vasomotion of the scaffolded vessel. Methods The ABSORB II trial is a prospective, randomised, active-controlled, single-blind, parallel two-group, multicentre clinical trial. We enrolled eligible patients aged years with evidence of myocardial ischaemia and one or two de-novo native lesions in different epicardial vessels. We randomly assigned patients (2:1) to receive treatment with an everolimus-eluting bioresorbable scaffold (Absorb; Abbott Vascular, Santa Clara, CA, USA) or treatment with an everolimus-eluting metallic stent (Xience; Abbott Vascular, Santa Clara, CA, USA). Randomisation was stratified by diabetes status and number of planned target lesions. At 3 year follow-up, the primary endpoint was superiority of the Absorb bioresorbable scaffold versus the Xience metallic stent in angiographic vasomotor reactivity after administration of intracoronary nitrate. The co-primary endpoint is the non-inferiority of angiographic late luminal loss. For the endpoint of vasomotion, the comparison was tested using a two-sided t test. For the endpoint of late luminal loss, non-inferiority was tested using a one-sided asymptotic test, against a non-inferiority margin of 0 14 mm. The trial is registered at ClinicalTrials.gov, number NCT Findings Between Nov 28, 2011, and June 4, 2013, we enrolled 501 patients and randomly assigned them to the Absorb group (335 patients, 364 lesions) or the Xience group (166 patients, 182 lesions). The vasomotor reactivity at 3 years was not statistically different (Absorb group mm [SD 0 109] vs Xience group mm [0 117]; p superiority =0 49), whereas the late luminal loss was larger in the Absorb group than in the Xience group (0 37 mm [0 45] vs 0 25 mm [0 25]; p non-inferiority =0 78). This difference in luminal dimension was confirmed by intravascular ultrasound assessment of the minimum lumen area (4 32 mm² [SD 1 48] vs 5 38 mm² [1 51]; p<0 0001). The secondary endpoints of patient-oriented composite endpoint, Seattle Angina Questionnaire score, and exercise testing were not statistically different in both groups. However, a device-oriented composite endpoint was significantly different between the Absorb group and the Xience group (10% vs 5%, hazard ratio 2 17 [95% CI ]; log-rank test p=0 0425), mainly driven by target vessel myocardial infarction (6% vs 1%; p=0 0108), including peri-procedural myocardial infarction (4% vs 1%; p=0 16). Interpretation The trial did not meet its co-primary endpoints of superior vasomotor reactivity and non-inferior late luminal loss for the Absorb bioresorbable scaffold with respect to the metallic stent, which was found to have significantly lower late luminal loss than the Absorb scaffold. A higher rate of device-oriented composite endpoint due to target vessel myocardial infarction, including peri-procedural myocardial infarction, was observed in the Absorb group. The patient-oriented composite endpoint, anginal status, and exercise testing, were not statistically different between both devices at 3 years. Future studies should investigate the clinical impact of accurate intravascular imaging in sizing the device and in optimising the scaffold implantation. The benefit and need for prolonged dual antiplatelet therapy after bioresorbable scaffold implantation could also become a topic for future clinical research. Funding Abbott Vascular. Introduction Interventional cardiologists have long been dreaming of a transient scaffold that would disappear after the job has been done. 1 Physiologically, the absence of a rigid metallic cage can facilitate the restoration of the vasomotor tone, adaptive shear stress, late luminal enlargement, and late expansive remodelling. Bioresorbable scaffold should not hamper pharmacologically induced plaque regression. Lancet 2016; 388: Published Online October 30, S (16) See Comment page 2451 The National Heart and Lung Institute, Imperial College London, London, UK (Prof P W Serruys MD); Institut Jacques Cartier, Massy, France (B Chevalier MD); Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands (Y Sotomi MD, Prof J J Piek MD); Bellvitge University Hôspital, Barcelona, Spain (A Cequier MD); Hopital de Rangueil, Toulouse, France (Prof D Carrié MD); Medical Center Leeuwarden, Leeuwarden, Netherlands (A J Van Boven MD); S Maria University Hospital, Terni, Italy (Prof M Dominici MD); Department of Interventional Cardiology, Jagiellonian University, Krakow, Poland (D Dudek MD); Christchurch Hospital, Christchurch, New Zealand (D McClean MD); Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (S Helqvist MD); Medical Clinic I, Städtische Klinken Neuss, Lukaskrankenhaus GmbH, Neuss, Germany (Prof M Haude MD); Universitätsklinikum der RWTH-Aachen, Germany (S Reith MD); Hospital Santa Cruz, Carnaxide, Portugal (M de Sousa Almeida MD); Cardiovascular Institute, Azienda Ospedaliero- Universitaria S Anna, Cona, FE, Italy (G Campo MD); Interventional Cardiology Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo, Spain (A Iñiguez MD); Thorax Institute, University Vol 388 November 19,

2 Hospital Clinic, Institut d Investigacions Biome diques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (M Sabaté MD); Universitätsklinik für Kardiologie, Inselspital, Bern, Switzerland (Prof S Windecker MD); ThoraxCenter, Erasmus Medical Center, Rotterdam, Netherlands (Y Onuma MD); and Cardialysis, Rotterdam, Netherlands (Y Onuma) Correspondence to: Prof P W Serruys, PO Box 2125, 3000 CC Rotterdam, Netherlands patrick.w.j.c.serruys@gmail. com Research in context Evidence before this study Bioresorbable scaffolds are a novel approach to treat coronary artery stenosis by providing transient scaffolding and local drug delivery. The potential of this technology, such as return of vasomotion, cyclic strain, and shear stress, has been shown in some observations at up to 3 years follow-up using multiple imaging modalities obtained in the ABSORB trials. We searched PubMed with the terms bioresorbable AND randomized between Jan 1, 1999, and Sept 24, 2016, for publications that reported randomised controlled trials, investigating the safety or efficacy of a bioresorbable scaffold compared with a metallic stent. Of 239 publications, four reported the design and rationale of the randomised trial. Two randomised trials (ABSORB Japan and ABSORB II) have reported their 1 year and 2 year follow-up and four randomised trials (EVERBIO II, TROFI II, ABSORB China, and ABSORB III) reported mid-term results up to 1 year. As of September, 2016, meta-analyses have shown non-inferiority at 1 year, but a statistically higher incidence of target vessel myocardial infarction was detected for the Absorb bioresorbable scaffold than the Xience metallic stent. Added value of this study This is the first randomised trial comparing a bioresorbable scaffold with a metallic stent in the treatment of coronary artery disease. The return of vasomotion with its potential benefit on late loss has been shown in a single observational group study, but has not been assessed in a randomised fashion versus a metallic drug-eluting stent. Beyond the report of the mechanistic primary endpoints, this is the first randomised trial reporting clinical events at 3 years, although the trial was not powered for clinical outcomes. Implications of all the available evidence The mechanistic part of the trial failed to show that the late luminal loss was comparable for the bioresorbable scaffold when compared with the metallic stent with a consequent increase of binary restenosis and rate of. Additionally, the incidence of very late scaffold thrombosis is a signal that warrants further careful monitoring of the patient having a clinical follow-up longer than 2 years. The benefit and need for prolonged dual antiplatelet therapy after bioresorbable scaffold implantation is at the present time entirely speculative. Bioresorbable scaffolds are suitable for non-invasive imaging such as computed tomography due to the absence of artifact caused by permanent radiopaque metallic material. At the time of the study design in July, 2011, commercialisation of a bioresorbable scaffold (Absorb; Abbott Vascular, Santa Clara, CA, USA) was just beginning, following approval with a CE mark in December, 2010; the use of the Absorb scaffold was in its infancy and the current recommendations regarding pre-dilation, device sizing, and post-dilation were not yet being applied. At that time, clinical evidence for the everolimus-eluting Absorb bioresorbable scaffold had been attained without the use of a comparator. There was a need to do a trial with the metallic comparator that was at that time the best-in-class drug-eluting stent. The aims of our trial were to assess the additional value of the technology by generating evidence-based data that would support the introduction of this novel device in clinical practice and to guide interventional cardiologists in its early use. Methods Study design and participants The ABSORB II trial is a prospective, randomised, active-controlled, single-blind, parallel group, multicentre clinical trial at 46 sites in Europe and New Zealand. We enrolled eligible patients aged years with evidence of myocardial ischaemia and one or two de-novo native lesions in different epicardial vessels. The protocol describing the inclusion criteria, exclusion criteria, the methods of quantitative coronary angiography, and intravascular ultrasound have been published previously. 2,3 A data safety monitoring board reviewed the cumulative safety data from the trial at given intervals for the purpose of safeguarding the interests of the participants. All patients provided informed consent before being included in the trial and all participating sites received medical ethics committee approval for the study. Patients had clinical follow-up at 30 days and 180 days and at 1, 2, and 3 years. Randomisation and masking Patients were randomly assigned (2:1) to either treatment with the everolimus-eluting bioresorbable scaffold (Absorb) or treatment with the everolimus-eluting metallic stent (Xience; Abbott Vascular, Santa Clara, CA, USA). Randomisation was by a centralised interactive voice web-based service and was stratified by diabetes status (diabetes vs no diabetes) and number of target lesions (single vs dual). Patients were masked to the treatment group for the duration of the trial. Study staff were instructed not to reveal the treatment to the patients or the referring physicians. Study investigators and physicians doing the procedure were not masked to treatment allocation. Procedures Repeat invasive imaging (sequential paired lesion analyses at baseline and at follow-up by either quantitative coronary angiography or intravascular ultrasound) was scheduled at 3 years for assessment of co-primary endpoints. In the case of repeat treatment of the target lesion, the luminal dimensions before the treatment were carried forward to Vol 388 November 19, 2016

3 501 patients in the study population 335 patients assigned to the Absorb group 364 lesions treated, QCA available for all pre-implantation and post-implantation 329 pre-implantation and 330 post-implantation IVUS 318 paired IVUS measurements 311 pre-implantation and post-implantation IVUS-VH 298 paired IVUS-VH measurements 166 patients assigned to the Xience group 182 lesions treated, QCA available for all pre-implantation and post-implantation 169 pre-implantation and 176 post-implantation IVUS 167 paired IVUS measurements 160 pre-implantation and post-implantation IVUS-VH 158 paired IVUS-VH measurements 1 patient withdrew consent after a clinical event 1 patient withdrew consent without a clinical event 333 patients had a 30 day clinical follow-up 166 patients had a 30 day clinical follow-up 2 patients withdrew consent after a clinical event 1 patient withdrew consent without a clinical event 1 patient died 1 patient withdrew consent without a clinical event 330 patients had a 180 day clinical follow-up 164 patients had a 180 day clinical follow-up 1 patient withdrew consent without a clinical event 1 patient withdrawn by physician without a clinical event 1 patient withdrew consent without a clinical event 328 patients had a 1 year clinical follow-up 163 patients had a 1 year clinical follow-up 3 patients withdrew consent without a clinical event 1 patient was lost to follow-up 4 patients died 3 patients withdrew consent without a clinical event 320 patients had a 2 year clinical follow-up 160 patients had a 2 year clinical follow-up 1 patient withdrew consent after a clinical event 1 patient withdrew consent without a clinical event 1 patient was lost to follow-up 4 patients died 5 patients died 313 patients had a 3 year clinical follow-up 298 lesions had QCA at follow-up (including 24 pre-tlr QCA carried forward) 258 lesions had vasomotion test 247 lesions had follow-up IVUS (including 11 pre-tlr IVUS carried forward) 244 paired IVUS measurements 212 paired IVUS-VH measurements 155 patients had a 3 year clinical follow-up 151 lesions had QCA at follow-up (including 8 pre-tlr QCA carried forward) 130 lesions had vasomotion test 136 lesions had follow-up IVUS (including 5 pre-tlr IVUS carried forward) 135 paired IVUS measurements 114 paired IVUS-VH measurements Figure 1: Trial profile QCA=quantitative coronary angiography. IVUS=intravascular ultrasound. IVUS-VH=intravascular ultrasound virtual histology. TLR=target lesion. the 3 year follow-up for statistical purposes. Angiography was documented before and after intracoronary administration of nitrate to assess vasomotion. Multiple matched angiographic views were used for the assessment of vasomotion and long-term luminal dimensions. 4,5 Seattle Angina Questionnaires were collected at preimplantation, and at follow-up at 180 days, 1, 2, and 3 years. 6 Exercise testing including ECG recording was done at 180 days, 1, 2, and 3 years. ST-T depression of 0 1 mv at maximal exercise or chest pain during exercise was considered as indicative of ischaemia. 7 Outcomes The co-primary endpoints at 3 years were vasomotion assessed by change in mean lumen diameter assessed by quantitative coronary angiography before and after Vol 388 November 19,

4 Absorb group Xience group Patients Number of patients Age (years) 61 5 (10 0) 60 9 (10 0) Sex Female 82 (24%) 34 (20%) Male 253 (76%) 132 (80%) Body-mass index (kg/m 2 ) 27 9 (4 1) 28 1 (3 7) Current tobacco use 79 (24%) 36 (22%) Hypertension (history or requiring 231 (69%) 119 (72%) medication or both) Dyslipidaemia (history or requiring 252 (75%) 133 (80%) medication or both) LDL cholesterol <2 mmol/l 113 (34 9) 51 (31 9) (80 mg/dl) All diabetes 80 (24%) 40 (24%) Diabetes mellitus treated with 22 (28%) 14 (35%) insulin Family history of premature coronary 112 (37%) 64 (41%) artery disease Previous cardiac intervention in 14 (12%) 5 (9%) target vessel Previous myocardial infarction 93 (28%) 48 (29%) Recent myocardial infarction with 11 (3%) 3 (2%) normalised enzyme Stable angina 214 (64%) 107 (64%) Stable angina Canadian 47 (14%) 24 (14%) Cardiovascular Society III or IV Unstable angina 68 (20%) 37 (22%) Unstable angina Braunwald class III 16 (24%) 10 (27%) Silent ischaemia 42 (13%) 19 (11%) Single vessel disease 278 (83%) 141 (85%) Target vessel Number of lesions Left anterior descending artery 163 (45%) 84 (46%) Left circumflex artery 106 (29%) 42 (23%) Right coronary artery 95 (26%) 56 (31%) Two or more target lesions treated 29/335 (9%) 16/166 (10%) Calcification (moderate or severe) 46 (13%) 28 (15 5) American College of Cardiology American Heart Association lesion class A 5 (1%) 1 (1%) B1 193 (53%) 90 (50%) B2 159 (44%) 87 (48%) C 6 (2%) 2 (1%) Data are n (%), n/n (%), n, or mean (SD), unless otherwise stated. Table 1: Characteristics of patients and lesions at baseline administration of intracoronary nitrate, and angiographic late luminal loss (minimum lumen diameter at followup after nitrate administration minus minimum lumen diameter post-procedure after nitrate administration). The co-primary endpoints were analysed in scaffolded and stented segments for the intention-to-treat populations, on a lesion basis. Intravascular ultrasound secondary endpoints were quantitative analysis of lumen area, plaque area, and vessel area. Outcomes measured for composite clinical secondary endpoints were death (cardiac vs vascular vs non-cardiovascular), myocardial infarction (Q wave vs non-q wave, attributable vs non-attributable to target vessel), target lesion, target vessel, non-target vessel, and all coronary s (all s clinically indicated vs non-clinically indicated). Composite clinical secondary endpoints were death plus all myocardial infarction; cardiac death plus myocardial infarction attributable to target vessel plus clinically indicated target lesion (device-oriented composite endpoint); and death plus all myocardial infarction plus all (patient-oriented composite endpoint). 8 Myocardial infarction per protocol was defined as the development of new pathological Q-wave or creatine kinase rise of two or more times the upper limit of normal accompanied by creatine kinase-mb rise. 2,3 The Seattle Patient Questionnaire and exercise testing were also secondary endpoints. Statistical analysis For the endpoint of vasomotion, the comparison was tested using a two-sided t test. For the endpoint of late luminal loss, non-inferiority was tested using a one-sided asymptotic test, against a non-inferiority margin of 0 14 mm. If non-inferiority was met with a higher value in the Absorb group, then superiority would be tested using a two-sided t test. A p value less than 0 05 was considered statistically significant. Sample size was calculated on the basis of the first co-primary endpoint (superiority for vasomotion). Assuming a two-tailed superiority t test, a 2:1 randomisation ratio, an α of 0 05, and true changes in mean lumen diameter of 0 07 mm for the Absorb scaffold and 0 mm for the Xience metallic stent (SD 0 20 mm for both), 9 14 we estimated that 260 lesions in the Absorb group and 130 lesions in the Xience group would be needed for 90% power. Allowing for a 29% attrition rate and 10% of patients with dual lesions, we estimated that 334 patients in the Absorb group and 167 patients in the Xience group would be needed. Considering the 390 lesions available for quantitative coronary angiography assessments, the study had 89% power to detect non-inferiority in the second co-primary endpoint of late luminal loss (assuming the true means are equal in both groups with an SD of 0 45 mm and a non-inferiority margin [δ] of 0 14 mm). The endpoint analyses presented in this report were done for an intention-to-treat population, on a lesion basis. Binary variables are summarised with counts and percentages, and for exact 95% CIs we used the Clopper-Pearson method. Continuous variables are summarised with means and SDs, and 95% CIs for the mean were calculated using the Gaussian Vol 388 November 19, 2016

5 approximation. χ² or Fisher s exact test was used to compare binary variables, and Student s t test or Wilcoxon signed-rank test was used to compare continuous variables. For time-to-event variables, survival curves were constructed using Kaplan-Meier estimates, and log-rank test results are for hypothesisgenerating purposes only. Analyses were done using SAS software version 9.3 (SAS Institute, Cary, NC, USA). The trial is registered at ClinicalTrials.gov, number NCT Role of the funding source The study funder was involved in study design, data collection, data analysis, data interpretation, and writing of this report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Results Between Nov 28, 2011, and June 4, 2013, we enrolled 501 patients and randomly assigned them to the Absorb group (335 patients, 364 lesions) or the Xience group (166 patients, 182 lesions; figure 1). Patient demographics and risk factors at baseline are shown in table 1. The prevalence of diabetes was 24%, with 7% in the Absorb group and 8% in the Xience group being insulin dependent. Overall, 21% of patients presented with unstable angina. More than 80% of patients had single-vessel disease. The complexity of the treated lesions is described according to the American Heart Association American College of Cardiology classification. Device success, procedural success, and the implantation technique have been previously reported. 6,7 The vasomotor reactivity test was analysable for 388 paired lesions (figure 1). At 3 year follow-up angio g raphy, the increase in mean lumen diameter after intracoronary injection of nitrate was not significantly different between the two groups (Absorb group [258 paired lesions] mm [SD 0 109] vs Xience group [130 paired lesions] mm [0 117]; p superiority =0 49). The criterion for superiority was not achieved. In both groups, the vasodilation of the proximal and distal edge was larger than the scaffolded or stented segment themselves (figure 2). Follow-up angiographic analysis was available for 298 lesions in the Absorb group and 151 lesions in the Xience group (table 2). Late luminal loss at 3 years was 0 37 mm (SD 0 45) in the Absorb group versus 0 25 mm (0 25) in the Xience group (p non-inferiority =0 78; figure 2). The criterion for non-inferiority was not met. Minimum lumen diameter at 3 years was 1 86 mm (SD 0 54) in the Absorb group versus 2 25 mm (0 37) in the Xience group (p<0 0001). Percentage diameter stenosis at follow-up was 25 84% (SD 17 26) in the Absorb group versus 15 72% (8 33) in the Xience group (p<0 0001). In-device binary restenosis was 7 0% (21 of 298 lesions) versus 0 7% (one of 151 lesions; p=0 0031) Cumulative frequency Cumulative frequency A Vasomotion (mm) B Absorb scaffold (scaffold) n=258, mm (SD 0 109) Xience stent (stent) n=130, mm (SD 0 117) Absorb scaffold (proximal) n=233, mm (SD 0 185) Xience stent (proximal) n=117, mm (SD 0 193) Absorb scaffold (distal) n=250, mm (SD 0 186) Xience stent (distal) n=124, mm (SD 0 241) p non-inferiority =0 78 p superiority = Xience stent n=151, 0 25 mm (SD 0 25) Absorb scaffold n=298, 0 37 mm (SD 0 45) Late luminal loss in-stent or in-scaffold (mm) Figure 2: Cumulative frequency distribution curves for the co-primary endpoints The absolute differences in mean lumen diameter (mm) before and after intracoronary nitrate injection (A) and late luminal loss (B) for the Absorb bioresorbable scaffold group and the Xience metallic stent group. in the Absorb group versus the Xience group, whereas in-segment binary restenosis was 8 4% (25 of 296 lesions) versus 3 3% (five of 151 lesions; p=0 0418). At 3-year follow-up, intravascular ultrasound was available for 247 lesions in the Absorb group and 136 lesions in the Xience group (table 2). Of 32 patients who had repeat target lesion, 19 had intravascular imaging before repeat treatment of target lesions, whereas the remaining 13 were not assessed. Acute gain in minimum lumen area post-procedure was on average significantly lower (2 89 mm² [SD 1 28] vs 3 64 mm² [1 28]; p<0 0001) and late luminal loss in minimum lumen area was on average significantly higher ( 0 56 mm² [1 11] vs 0 33 mm² [0 97]; p=0 0401) in the Absorb group than in the Xience group. Minimum Vol 388 November 19,

6 Absorb group Xience group Difference (95% CI) p value Angiographic analysis Number of lesions Lesion length obstruction (mm) (6 65) (6 01) 0 54 ( 0 69 to 1 77) 0 39 Total scaffolded or stented length (mm) (9 07) (6 96) 0 35 ( 1 18 to 1 88) 0 66 In-scaffold or stent assessment Reference vessel diameter Pre-procedure diameter (mm) 2 59 (0 39) 2 61 (0 40) ( to ) 0 70 Post-procedure diameter (mm) 2 64 (0 36) 2 79 (0 34) 0 15 ( 0 21 to 0 08) < Follow-up diameter (mm) 2 50 (0 40) 2 67 (0 34) 0 17 ( 0 24 to 0 10) < Minimum lumen diameter Pre-procedure diameter (mm) 1 06 (0 33) 1 06 (0 31) 0 01 ( 0 05 to 0 07) 0 81 Post-procedure diameter (mm) 2 22 (0 33) 2 50 (0 33) 0 28 ( 0 34 to 0 21) < Acute gain (mm) 1 16 (0 38) 1 45 (0 37) 0 29 ( 0 36 to 0 21) < Follow-up diameter (mm) 1 86 (0 54) 2 25 (0 37) 0 39 ( 0 48 to 0 31) < Percent diameter stenosis Pre-procedure percent diameter stenosis (%) (11 31) (11 42) 0 25 ( 2 49 to 1 99) 0 83 Post-procedure percent diameter stenosis (%) (6 63) (4 85) 5 55 (4 47 to 6 64) < Follow-up percent diameter stenosis (%) (17 26) (8 33) (7 75 to 12 50) < Binary restenosis (%) 7 0% (4 41 to 10 57) 0 7% (0 02 to 3 63) 6 38% (2 55 to 9 91) Net gain (mm) 0 80 (0 61) 1 20 (0 44) 0 41 ( 0 51 to 0 31) < In-segment assessment Minimum lumen diameter Post-procedure 2 06 (0 37) 2 15 (0 42) 0 09 ( 0 17 to 0 01) years 1 78 (0 51) 2 02 (0 40) 0 24 ( 0 33 to 0 15) < In-segment late loss 0 29 (0 46) 0 14 (0 34) 0 15 ( 0 22 to 0 07) Binary restenosis (%) 8 4% (5 50 to 12 14) 3 3% (1 08 to 7 56) 5 08% (0 11 to 9 23) Co-primary endpoints Vasomotion (mm) (0 109) (0 117) ( to ) 0 49* In-stent or scaffold late loss (mm) 0 37 (0 45) 0 25 (0 25) 0 12 (0 06 to 0 19) 0 78, Greyscale intravascular ultrasonographic analysis in scaffolded or stented segment Number of lesions Mean vessel area Pre-procedure area (mm 2 ) (3 43) (3 22) 0 93 ( 1 64 to 0 22) Post-procedure area (mm 2 ) (3 51) (3 35) 1 21 ( 1 93 to 0 50) Follow-up area (mm 2 ) (3 66) (3 33) 0 77 ( 1 50 to 0 05) Mean total plaque area Pre-procedure plaque area/media (mm 2 ) 6 61 (2 49) 7 32 (2 41) 0 71 ( 1 23 to 0 18) Post-procedure plaque area/media (mm 2 ) 6 99 (2 40) 7 44 (2 23) 0 45 ( 0 93 to 0 03) 0 07 Follow-up plaque area/media (mm 2 ) 7 66 (2 27) 7 90 (2 15) 0 24 ( 0 70 to 0 22) 0 31 Mean lumen area Pre-procedure mean lumen area (mm 2 ) 4 81 (1 41) 5 02 (1 38) 0 22 ( 0 52 to 0 08) 0 16 Post-procedure mean lumen area (mm 2 ) 6 05 (1 45) 6 81 (1 52) 0 76 ( 1 08 to 0 45) < Follow-up mean lumen area (mm 2 ) 6 12 (1 88) 6 66 (1 53) 0 54 ( 0 89 to 0 19) Minimal lumen area Pre-procedure minimal lumen area (mm 2 ) 2 01 (0 71) 2 11 (0 79) 0 09 ( 0 26 to 0 07) Post-procedure minimal lumen area (mm 2 ) 4 88 (1 39) 5 72 (1 46) 0 84 ( 1 14 to 0 53) < Acute gain in minimal lumen area (mm 2 ) 2 89 (1 28) 3 64 (1 28) 7 54 ( 1 03 to 0 48) < (Table 2 continues on next page) Vol 388 November 19, 2016

7 Absorb group Xience group Difference (95% CI) p value (Continued from previous page) Follow-up minimal lumen area (mm 2 ) 4 32 (1 48) 5 38 (1 51) 1 06 ( 1 38 to 0 75) < Mean change in minimal lumen area from 0 56 (1 11) 0 33 (0 97) 0 23 ( 0 44 to 0 01) post-procedure to 3 years (mm 2 ) Incomplete malapposition area (mm 2 ) 2 18, n= (1 18), n= ( to ) 0 59 Major secondary endpoint Mean change in mean lumen area from post-procedure to 3 years (mm 2 ) 0 07 (1 20) 0 15 (0 69) 0 23 (0 04 to 0 42) Virtual histology analysis in scaffolded or stented segment Number of lesions Pre-procedural dense calcium (%) 4 92 (4 94) 4 22 (3 60) 0 70 ( 0 26 to 1 67) 0 15 Pre-procedural necrotic core (%) (6 99) (6 18) 0 66 ( 0 86 to 2 18) 0 39 Post-procedural dense calcium (%) 6 28 (3 54) 8 79 (3 46) 2 50 ( 3 30 to 1 70) < Post-procedural necrotic core (%) (4 70) (4 03) 1 40 ( 2 37 to 0 42) year dense calcium (%) 5 47 (3 49) (4 72) 5 76 ( 6 75 to 4 76) < year necrotic core (%) (4 11) (3 86) 4 30 ( 5 20 to 3 40) < Data are n (%) or mean (SD), unless otherwise stated. *p for superiority. p for non-inferiority. p for difference. Calculated as a mean within the lesions with malapposition. Table 2: Angiographic and intravascular ultrasound analyses before and after the procedure, and at 3 year follow-up Absorb group Xience group Difference (95% CI) p value Participated in exercise test 239/335 (71%) 120/166 (72%) 0 95% ( 8 99 to 7 63) 0 83 Participated in exercise test: patients with 203/335 (61%) 93/166 (56%) 4 57% ( 4 49 to 13 72) 0 33 exercise test and no previous repeat Treadmill 110/203 (54%) 48/91 (53%) 1 44% ( to 13 62) 0 82 Cycling 93/203 (46%) 43/91 (47%) 1 44% ( to 10 64) 0 82 Maximum heart rate (beats per min) (21 3) (21 0) 5 2 ( 10 4 to 0 1) Diastolic blood pressure at peak exercise 79 5 (14 7) 83 9 (20 2) 4 4 ( 9 1 to 0 3) 0 07 (mm Hg) Systolic blood pressure at peak exercise (29 8) (28 5) 3 8 ( 11 1 to 3 5) 0 30 (mm Hg) Maximum workload (watts) (44 49), n= (39 16), n= ( to 4 71) 0 17 Maximum workload (metabolic 8 92 (2 82), n= (2 74), n= ( 1 83 to 0 02) equivalents) Terminated by physician due to 2/50 (4%) 0/ % ( to 13 46) 1 0 >0 2 mv ST depression Test terminated by patient (dyspnoea) 22/138 (16%) 7/67 (10%) 5 49% ( 5 40 to 14 28) 0 29 Test terminated by patient (angina) 2/138 (1%) 3/67 (4%) 3 03% ( to 1 68) 0 33 Exercise duration (min) 8 57 (3 36) 9 23 (3 27) 0 66 ( 1 48 to 0 16) mv ST depression 28/201 (14%) 7/93 (8%) 6 40% ( 1 89 to 13 08) 0 11 Chest pain during exercise 9/202 (4%) 4/93 (4%) 0 15% ( 6 43 to 4 76) mV ST depression or chest pain 35/202 (17%) 11/93 (12%) 5 50% ( 3 83 to 13 23) 0 23 Antianginal medication at 3 years β blocker 141/203 (69%) 60/91 (66%) 3 52% ( 8 09 to 15 14) 0 55 Calcium-channel blocker 48/203 (24%) 22/91 (24%) 0 53% ( to 10 03) 0 92 Nitrate 38/203 (19%) 24/91 (26%) 7 65% ( to 2 87) 0 14 Data are n (%) or mean (SD) unless otherwise stated. Table 3: Exercise test (intention-to-treat population, excluding tests subsequent to any ) lumen area at 3 year follow-up was significantly smaller in the Absorb group than in the Xience group (4 32 mm² [SD 1 48] vs 5 38 mm² [1 51]; p<0 0001). Post-procedure, the mean lumen area in the Xience group was significantly larger than in the Absorb group (6 05 mm² [SD 1 45] vs 6 81 mm² [1 52]; p<0 0001). Vol 388 November 19,

8 Absorb group Xience group Seattle Angina Questionnaire score * 0 96* 0 98* 0 79* 0 82* Baseline Month 6 Year 1 Year 2 Year 3 Baseline Month 6 Year 1 Year 2 Year 3 Baseline Month 6 Year 1 Year 2 Year 3 Baseline Month 6 Year 1 Year 2 Year 3 Baseline Month 6 Year 1 Year 2 Year 3 Baseline Month 6 Year 1 Year 2 Year 3 % angina free Angina frequency Angina stability Physical limitation Quality of life Treatment satisfaction Figure 3: Responses to the Seattle Angina Questionnaire The five domains of the Seattle Angina Questionnaire relate to angina stability, angina frequency, physical limitation, disease perception (ie, quality of life), and treatment satisfaction in addition to number of patients with no angina. Bars show 95% CIs. *p value from post-hoc test. p value from χ 2 test. See Online for appendix At follow-up, there were no changes in the mean lumen area of the Absorb group (+0 07 mm² [SD 1 20]; p=0 54), whereas there was a significant decrease in the mean lumen area of the Xience group ( 0 15 mm² [0 70]; p=0 0095). Serial intravascular ultrasound follow-up (a prespecified major secondary imaging endpoint) showed a significant difference between the stable mean lumen area in the Absorb group and the Xience group (+0 07 mm² [SD 1 20] vs 0 15 mm² [0 69]; p=0 0190). As a surrogate for bioresorption, the upper and hyper echogenicity significantly decreased from 13 8% [SD 4 7] at baseline to 11 6% [5 6] at 3 years (p<0 0001). Analysis of exercise testing was prespecified in the protocol. 359 (72%) patients received an exercise test at 3 years (table 3). Electrocardiographic signs and symptoms among the patients without previous repeat (n=296, 59%) were not statistically different between both groups ( 0 1 mv ST depression or chest pain, 35 [17%] of 202 in the Absorb group vs 11 [12%] of 93 in the the Xience group; p=0 23). Figure 3 shows the five domains of the Seattle Angina Questionnaire related to angina stability, frequency, physical limitation, disease perception, and treatment satisfaction. Substantial improvement in every domain at 3 years was documented with respect to the preprocedural assessment without significant difference between the two treatment groups. Before the procedure, 94 patients (29%) subsequently assigned to the Absorb group and 48 patients (29%) subsequently assigned to the Xience group, were free from angina, whereas at 3 years, 230 (74%) patients in the Absorb group and 113 (73%) patients in the Xience group were free from angina. Clinical follow-up was available for 313 patients (93%) in the Absorb group and 155 patients (93%) in the Xience group. 16 patients withdrew their consent, one patient was withdrawn by the physician, two patients were lost to follow-up, and 14 patients died (figure 1). The overall death rate was 2% in the Absorb group and 4% in the Xience group (p=0 57), whereas the overall rates of myocardial infarction were 8% in the Absorb group and 3% in the Xience group (p=0 0295). Table 4 and figure 4 report the patient-oriented and device-oriented composite endpoints. The device-oriented composite endpoint was significantly higher in the Absorb group than in the Xience group (10% vs 5%; hazard ratio 2 17 [95% CI ]; p=0 0425; figure 4), driven by target vessel myocardial infarction in the Absorb group (6% vs 1%; p=0 0108), 52% of which was peri-procedural (4% vs 1%; p=0 16), based on the per-protocol and historical definition of WHO. In the Xience group, there was only peri-procedural target vessel myocardial infarction. 3 year protocol-mandated imaging triggered subsequent s, clinically indicated or not (figure 4). Over 3 years, there were eight definite scaffold thromboses (one acute, one subacute, six very late) and one late probable scaffold thrombosis in the Absorb group (3%), and no definite or probable stent thrombosis in the Xience group (p=0 0331). Baseline characteristics, risk factors, clinical presentation, anginal status, pharmacological treatment, and procedural results by angiography and intravascular ultrasound of these cases are shown in the appendix). These nine scaffold Vol 388 November 19, 2016

9 Absorb group Xience group Relative risk (95% CI) Difference (95% CI) p value Secondary endpoints All deaths 8/325 (2%) 6/161 (4%) 0 66 (0 23 to 1 87) 1 27% ( 5 60 to 1 80) 0 57 Cardiac deaths 3/325 (1%) 3/161 (2%) 0 50 (0 10 to 2 43) 0 94% ( 4 46 to 1 20) 0 40 Myocardial infarction per protocol 27/325 (8%) 5/161 (3%) 2 68 (1 05 to 6 82) 5 20% (0 50 to 9 13) Q wave 10/325 (3%) 2/161 (1%) 2 48 (0 55 to 11 17) 1 83% ( 1 63 to 4 49) 0 35 Non-Q wave 17/325 (5%) 3/161 (2%) 2 81 (0 83 to 9 44) 3 37% ( 0 61 to 6 60) 0 08 Target vessel myocardial infarction 23/325 (7%) 2/161 (1%) 5 70 (1 36 to 23 87) 5 83% (1 91 to 9 27) Q wave myocardial infarction 9/325 (3%) 0/161 NA 2 77% (0 10 to 5 18) Non-Q wave myocardial infarction 14/325 (4%) 2/161 (1%) 3 47 (0 80 to 15 07) 3 07% ( 0 55 to 6 00) 0 07 Non-target vessel myocardial infarction 4/325 (1%) 3/161 (2%) 0 66 (0 15 to 2 92) 0 63% ( 4 18 to 1 62) 0 69 Q wave myocardial infarction 1/325 (<1%) 2/161 (1%) 0 25 (0 02 to 2 71) 0 93% ( 4 12 to 0 74) 0 26 Non-Q wave myocardial infarction 3/325 (1%) 1/161 (<1%) 1 49 (0 16 to 14 17) 0 30% ( 2 58 to 2 13) 1 0 All target lesion 24/325 (7%) 8/161 (5%) 1 49 (0 68 to 3 23) 2 42% ( 2 70 to 6 57) 0 31 Clinically indicated target lesion 20/325 (6%) 3/161 (2%) 3 30 (1 00 to 10 95) 4 29% (0 22 to 7 68) Non-clinically indicated target lesion 4/325 (1%) 5/161 (3%) 0 40 (0 11 to 1 46) 1 87% ( 5 90 to 0 72) 0 17 All target vessel 33/325 (10%) 19/161 (12%) 0 86 (0 51 to 1 46) 1 65% ( 8 19 to 3 93) 0 58 Clinically indicated target vessel 23/325 (7%) 12/161 (7%) 0 95 (0 48 to 1 86) 0 38% ( 6 00 to 4 19) 0 88 Non-clinically indicated target vessel 11/325 (3%) 11/161 (7%) 0 50 (0 22 to 1 12) 3 45% ( 8 65 to 0 49) 0 09 Non-target vessel 22/325 (7%) 19/161 (12%) 0 57 (0 32 to 1 03) 5 03% ( to 0 22) 0 06 Clinically indicated non-target vessel 17/325 (5%) 15/161 (9%) 0 56 (0 29 to 1 10) 4 09% ( 9 90 to 0 58) 0 09 Non-clinically indicated non-target vessel 8/325 (2%) 7/161 (4%) 0 57 (0 21 to 1 53) 1 89% ( 6 40 to 1 33) 0 27 All 49/325 (15%) 33/161 (20%) 0 74 (0 49 to 1 10) 5 42% ( to 1 57) 0 13 Clinically indicated 36/325 (11%) 25/161 (15%) 0 71 (0 44 to 1 15) 4 45% ( to 1 71) 0 16 Non-clinically indicated 18/325 (6%) 18/161 (11%) 0 50 (0 27 to 0 93) 5 64% ( to 0 62) Composite secondary endpoints Cardiac death, target vessel myocardial infarction, 34/325 (10%) 8/161 (5%) 2 11 (1 00 to 4 44) 5 49% (0 13 to 10 00) and clinically indicated target lesion (target lesion failure; device-oriented composite endpoint) Cardiac deaths* 3/325 (1%) 3/161 (2%) 0 50 (0 10 to 2 43) 0 94% ( 4 46 to 1 20) 0 40 Target vessel myocardial infarction* 21/325 (6%) 2/161 (1%) 5 20 (1 23 to 21 91) 5 22% (1 36 to 8 56) Clinically indicated target- lesion 10/325 (3%) 3/161 (2%) 1 65 (0 46 to 5 92) 1 21% ( 2 53 to 3 99) 0 56 * All death, all myocardial infarction, and all 68/325 (21%) 39/161 (24%) 0 86 (0 61 to 1 22) 3 30% ( to 4 33) 0 41 (patient-oriented composite endpoint) All deaths* 8/325 (2%) 6/161 (4%) 0 66 (0 23 to 1 87) 1 27% ( 5 60 to 1 80) 0 57 All myocardial infarction* 25/325 (8%) 5/161 (3%) 2 48 (0 97 to 6 35) 4 59% ( 0 06 to 8 44) All * 35/325 (11%) 28/161 (17%) 0 62 (0 39 to 0 98) 6 62% ( to 0 26) (Table 4 continues on next page) thromboses were associated with ST elevation myocardial infarction, and one patient died 13 days after a scaffold thrombosis. Discussion At 3 years, the Absorb bioresorbable scaffold did not show superior vasomotor reactivity and did not show non-inferior angiographic late luminal loss compared with the Xience metallic stent, despite a significant difference between the stable mean lumen area in the intravascular ultrasound of the Absorb group and a significant loss in mean lumen area in the Xience group. The device-oriented composite endpoint was higher in the Absorb group, mainly due to target vessel myocardial infarction including peri-procedural myocardial infarction. The patient-oriented composite endpoint, anginal status, and exercise testing performance, were not statistically different between both groups at 3 years. Vol 388 November 19,

10 Absorb group Xience group Relative risk (95% CI) Difference (95% CI) p value (Continued from previous page) Thrombosis endpoints Definite scaffold or stent thrombosis 8/320 (3%) 0/159 NA 2 50% ( 0 16 to 4 85) 0 06 Acute (0 1 day) 1/335 (<1%) 0/166 NA 0 30% ( 1 98 to 1 67) 1 0 Sub-acute (2 30 days) 1/334 (<1%) 0/166 NA 0 30% ( 1 98 to 1 68) 1 0 Late ( days) 0/329 0/164 NA 0 00% ( 2 29 to 1 15) 1 0 Very late (>365 days) 6/329 (2%) 0/164 NA 1 82% ( 0 67 to 3 92) 0 19 Definite or probable scaffold or stent thrombosis 9/320 (3%) 0/159 NA 2 81% (0 11 to 5 26) Acute (0 1 day) 1/335 (<1%) 0/166 NA 0 30% ( 1 98 to 1 67) 1 0 Sub-acute (2 30 days) 1/334 (<1%) 0/166 NA 0 30% ( 1 98 to 1 68) 1 0 Late ( days) 1/329 (<1%) 0/164 NA 0 30% ( 2 00 to 1 70) 1 0 Very late (>365 days) 6/329 (2%) 0/164 NA 1 82% ( 0 67 to 3 92) 0 19 Patients on dual antiplatelet therapy at day /334 (31%) 49/166 (30%) NA 1 02% ( 7 69 to 9 24) 0 81 Duration of dual antiplatelet therapy within 1095 days (days) (324 2), n= (319 1), n=166 NA 4 5 ( 55 5 to 64 4) 0 88 Data are n/n (%), unless stated otherwise. Denominators exclude patients who were lost to follow-up or who withdrew consent, except for those who died or experienced the corresponding endpoint before their withdrawal of consent. NA=not available. *Numbers are hierarchical counts in the composite endpoints. Table 4: Secondary clinical outcomes at 3 year follow-up In designing the present randomised trial, the assumption was made that the metallic stent would not exhibit vasomotion as previously reported in the literature. 10,11,13,14 The overall vasodilation of the scaffold observed in the present study (0 047 mm [SD 0 11]) is very similar to the vasodilation observed in the first-inman study at 3 years (0 054 mm [0 12]) 12 and in the ABSORB Japan randomised trial at 2 years (0 06 mm [0 14]). 15 Future trials might consider alternative imaging, different vasodilator responses, or later follow-up to confirm whether there is a true vasomotor advantage for the bioresorbable scaffold or whether this proposed benefit is not realised in practice when compared with contemporary metallic drugeluting stents. The angiographic in-scaffold late luminal loss at 3 years in the present study (0 37 mm [SD 0 45]) is larger than the late luminal loss (0 29 mm [0 43]) observed in the first-in-man trial, 12 but comparable with the 2 year late luminal loss (0 36 mm [0 38]) reported in the ABSORB Japan trial. 15 Comparative measurement of luminal dimension obtained by angiography immediately after implantation of Absorb and Xience has been flawed by methodological bias in quantification, with a systematic underestimation of the scaffolded lumen dimension due to thick polymeric struts when compared with the stented lumen with thin metallic struts. 16 Nevertheless, at follow-up in both cases the comparative method is again reliable since the endoluminal lining consists of a continuous layer of neointimal tissue covering the polymeric and metallic struts. Therefore, the minimum lumen diameter on angiography and minimum lumen area on intravascular ultrasound at follow-up must be considered as objective assessments of the respective performance of the two devices. Difference in device volume and backscattering between the polymeric scaffolds and metallic stents are known to affect the intravascular ultrasound assessment of the immediate change in plaque media and lumen volume post-procedure differently, and might together with the difference in balloon diameter and inflation pressure partially explain the significant difference in mean and minimum lumen area immediately after the procedure. 3,17 However, at 3 year follow-up, this methodological bias should no longer interfere with the intravascular ultrasound assessment of luminal dimension for the same above-mentioned reasons. Therefore, the minimum lumen area in the Absorb group is objectively smaller than in the Xience group. The acute procedural relative under-expansion of the Absorb scaffolds compared with the Xience stents as previously reported 3 could theoretically affect the long-term outcomes. In this study the very late lumen size at 3 years for the Absorb scaffold was compromised by the relative under-expansion at baseline, which is very different from what is being observed in clinical practice with the proper lesion preparation, adequate sizing, and systematic post-dilation. Future studies will be needed to show the effect of these new implant techniques on late outcomes. Serial intravascular ultrasound follow-up showed a significant difference between the stable mean lumen area of the Absorb scaffold and a significant loss in mean lumen area for the Xience metallic stent. As previously shown in the first-in-man trial, the mean lumen area in the Absorb group enlarged with time, whereas in the Xience group it decreased significantly. In the first-in-man trial of Absorb, the minimum lumen area remained unchanged, whereas in the present trial, there was a significant loss in minimum lumen area. The sequential intravascular ultrasound measurements in the first-in-man trial Vol 388 November 19, 2016

11 indicated that substantial change in vessel area, plaque media, and lumen area still occurred between 3 and 5 years (ie, the complete wall dynamic change resulting from bioresorption of the scaffold can only be fully assessed at 5 years 18 ). The clinical performance of the two groups was not significantly different in terms of the patient-oriented composite endpoint, the exercise test, and patient-reported outcomes as assessed by the Seattle Angina Questionnaire. However, in the patient-oriented composite endpoint, the rate of non-clinically indicated was doubled in the Xience group compared with the Absorb scaffold group. The findings of higher non-clinically driven target lesion or vessel rates for the Xience stent could be attributed to the unmasked nature of the intervention despite the protocol recommendation of masking the patient. Unmasked physicians could be prone to readily re-intervene in the control group of patients treated with the Xience stent, whereas they might have been unconsciously reluctant to intervene in the experimental device group (Absorb scaffold), although this assumption is purely speculative and has not been objectively documented. In the Absorb group, there were 23 (7%) adjudicated target vessel myocardial infarctions of which 13 were peri-procedural, which was adjudicated according to the WHO definition. Using these criteria, the peri-procedural myocardial infarction rate in the current trial was 4% in the Absorb group versus 1% in the Xience group, whereas it was 0 6% in both groups when the more contemporary Society for Cardiovascular Angiography and Interventions definition was applied. 3,19 When post-hoc landmark analysis was done at 30 days to assess the performance of the devices without taking into account the incidence of peri-procedural myocardial infarction, the rates of deviceoriented composite endpoints for the Absorb group versus the Xience group were 6 5% versus 3 7% (appendix). Further evolution of comparative device performances after 3 years should be investigated in large-scale long-term randomised trials. There were six definite very late scaffold thromboses reported between 1 and 3 years. In the most recent systematic review, 16 very late scaffold thromboses from ten studies (n=2311) were reported; 20 the mean follow-up was 28 months (SD 11; median 24 months [minimum 24, maximum 60]), the overall weighted rate of very late definite and probable scaffold thrombosis was 1 0% (95% CI ), and all very late events were definite scaffold thrombosis. In an allcomer registry (n=4212 patients), the reported incidence rate per 100 patient-years of very late definite Xience stent thrombosis up to 4 years is 0 6%. 21 In the present study, no systematic optical coherence tomography or ultrasound imaging was done at the time of event in an attempt to understand the mechanistic aetiology of the very late scaffold thrombosis. One single case investigated with optical Patient-oriented clinical endpoint (%) Absorb Number at risk % event rate % SEM Xience Number at risk % event rate % SEM Device-oriented clinical endpoint (%) Absorb Number at risk % event rate % SEM Xience Number at risk % event rate % SEM A HR (95% CI) 0 86 ( ); log-rank p= B Absorb group Xience group Figure 4: Kaplan-Meier curves for the patient-oriented (A) and device-oriented (B) composite clinical endpoints The device-oriented composite endpoint was cardiac death plus myocardial infarction attributable to target vessel plus clinically indicated target lesion. The patient-oriented composite endpoint was death plus all myocardial infarction plus all. SEM=standard error of mean. coherence tomography showed at the site of throm bosis a marked eccentricity of the lumen that was not present post-procedure. Incomplete lesion coverage, malapposition, strut discontinuities, and under-expansion of the scaffold have been observed by optical coherence tomography in patients treated with Absorb with definite very late scaffold thrombosis In the present study, the analysis of the post-implantation results did not raise any concern on the performance of the implantation, since the reference diameter, proximal % r=3 2% 20 8% Time after index procedure (days) HR (95% CI) 2 17 ( ); log-rank p= % r=5 5% 4 9% Time to event (days) Time after index procedure (days) Vol 388 November 19,