Vascular response to percutaneous coronary intervention with biodegradable-polymer vs. new-generation durable-polymer drug-eluting stents: a meta-analysis of optical coherence tomography imaging trials

Vascular response to percutaneous coronary intervention with biodegradable-polymer vs.... Abstract Aims Whether biodegradable-polymer drug-eluting stents (BP-DES) induce a vascular response at follow-up more favourable than that of new-generation durable-polymer drug-eluting stents (DP-DES) remains controversial. We sought to evaluate the vascular response to percutaneous coronary intervention (PCI) with BP-DES vs. new-generation DP-DES as assessed by optical coherence tomography (OCT) imaging at follow-up. Methods and results We undertook a meta-analysis of aggregate data by searching electronic scientific databases for investigations of PCI-patients receiving BP-DES vs. new-generation DP-DES and OCT imaging at follow-up. The primary outcome was neointima hyperplasia (NIH) thickness. The co-primary outcome was the incidence of lesions with uncovered struts. The main secondary outcome was the incidence of lesions with malapposed struts. Among 10 trials, a total of 544 PCI-patients were assigned to BP-DES (n = 282) or new-generation DP-DES (n = 262). Of these, 447 participants with 480 treated lesions had analysable OCT imaging at a weighted median follow-up of 7 months. Lesions treated with BP-DES vs. new-generation DP-DES showed comparable NIH thickness [weighted mean difference 95% confidence intervals (CI)  = −11.37 (−29.25, 6.52); P = 0.21]. However, thick-struts (>100 μm) BP-DES showed less NIH thickness as compared to new-generation DP-DES [−20.39 (−33.83, −6.95); P = 0.003]. BP-DES vs. new-generation DP-DES showed a higher risk for uncovered struts [odds ratio 95% CI = 3.50 (1.69–7.26); P = 0.0008] and a trend towards higher risk for malapposed struts [2.01 (0.98–4.12); P = 0.06]. Conclusion In PCI-patients with available OCT imaging at follow-up, BP-DES with thicker backbones delay vascular response as compared with new-generation DP-DES. biodegradable polymer, drug-eluting stent, durable polymer, meta-analysis, optical coherence tomography, percutaneous coronary intervention Introduction The peculiarity of biodegradable-polymer drug-eluting stents (BP-DES) is that once the anti-restenotic drug is eluted and the carrier completely degraded, the stent platform left behind resembles that of a bare metal stent. By virtue of the transient nature of the carrier, these modern devices for percutaneous coronary intervention (PCI) should elicit a more physiological vascular response in comparison to durable-polymer drug-eluting stents (DP-DES).1 Previous clinical investigations found improved healing and lower thrombogenicity with BP-DES compared to early-generation DP-DES.2 However, the favourable vascular behaviour of BP-DES was not confirmed in comparisons against new-generation DP-DES.3 Optical coherence tomography (OCT) is an innovative tool for high-resolution intravascular imaging. By providing near histology-level images, OCT has been used to unravel the coronary response following stenting.4 Since difference in stent platform, biocompatibility, and degradation kinetics of polymers may impact the healing patterns of stented coronary segments and the inherent risk for adverse outcomes, investigations of vascular response after PCI with BP-DES vs. new-generation DP-DES may be a matter of clinical interest. In light of inconsistent results of recent imaging studies dealing with this topic,5–8 we performed a meta-analysis of trials evaluating the vascular response after PCI with BP-DES or new-generation DP-DES, as measured by OCT imaging at follow-up. Methods Search strategy and selection criteria We searched Medline, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), scientific sessions abstracts, and relevant websites (www.cardiosource.com, www.clinicaltrialresults.org, www.escardio.org, www.tctmd.com, www.theheart.org) for investigations of PCI-patients assigned to BP-DES or new-generation DP-DES and OCT imaging at follow-up. The reference lists from two previous meta-analyses9,10 evaluating vascular response with OCT after coronary stenting were checked to identify further citations. For this report, stent platforms other than early-generation sirolimus-eluting stents (SES/Cypher, Cordis, Warren, NJ, USA), paclitaxel-eluting stents (Taxus, Boston Scientific, Natick, MA, USA) and fast-release zotarolimus-eluting stents (ZES/Endeavor, Medtronic, Santa Rosa, CA, USA) were considered new-generation DP-DES. Search terms included the keywords and the corresponding Medical Subject Headings for: ‘drug-eluting stent(s)’, ‘biodegradable polymer’, ‘durable polymer’, ‘OCT’, ‘trial’, and ‘randomized trial’. No restrictions concerning language or publication status were imposed. Inclusion criteria were (i): OCT imaging performed between ≥1 and 12 months after BP-DES or new-generation DP-DES implantation; and (ii) description of OCT imaging protocols. Comparisons other than BP-DES vs. new-generation DP-DES were ineligible. We performed the last search of scientific databases for articles dealing with the topic under investigation on 17 May 2017. The reference lists from all eligible studies were checked to identify further citations. Data collection and assessment of risk of bias Two investigators (SC and EX) independently assessed publications for eligibility at the title and/or abstract level. Divergences were resolved by consensus. Studies that met inclusion criteria were selected for further analysis. Risk of bias was independently evaluated for each study by the same two investigators in accordance with The Cochrane Collaboration method.11 Composite quality scores were not assigned.12 Outcomes The primary outcome of the current report was neointima hyperplasia (NIH) thickness and the co-primary outcome was the incidence of lesions with uncovered struts. The main secondary outcome was the incidence of lesions with malapposed struts. Other secondary outcomes of interest were NIH area, NIH volume and target lesion/vessel revascularization (TLR/TVR). All endpoints were evaluated in accordance with intention-to-treat principle and definitions reported in the original protocols. Statistical analysis Odds ratio and the weighted mean difference with 95% confidence intervals were used to compare the outcomes of interest between BP-DES and new-generation DP-DES and pooled using the Mantel–Haenszel random-effect model (DerSimonian and Laird). Heterogeneity between trials was quantified using the I2 statistic accompanied by a χ2 test: I2 values around 25%, 50%, and 75% were suggested to indicate low, moderate, or high heterogeneity, respectively.13 In addition, we estimated the between-study variance (τ2). The possibility of small study effects resulting from publication bias or other biases was examined for main primary outcome by means of visual inspection of funnel plots of the ORs of individual trials against their standard errors, accompanied by a statistical test of asymmetry.14 An influence analysis, in which meta-analysis estimates are computed omitting one study at a time, was performed for the risk estimation of main primary outcome. Using a χ2 test for subgroup by treatment interaction, we determined whether certain covariates were associated with risk estimation for the main primary outcome. The covariates investigated were: the time-point of OCT imaging (≤6 months vs. >6 months after index PCI), the strut thickness (≤100 μm vs. >100 μm) or the antiproliferative drug (sirolimus vs. biolimus) of BP-DES platforms, the minimum number of participants in each included trial (≤40 patients vs. >40 patients), and the inclusion of patients with diabetes (yes vs. no) or acute MI (yes vs. no). This study was reported in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement (see Supplementary data online).15 All analyses were performed in RevMan (Review Manager, Version 5.3, The Cochrane Collaboration, Copenhagen, Denmark) and R (version 3.3.2; R Foundation for Statistical Computing, Vienna, Austria). This study is registered with PROSPERO, number CRD42017067525. Results The electronic search identified 10 studies, all with full-length articles,5–8,16–21 in which PCI-patients were assigned to BP-DES or new-generation DP-DES and subsequent OCT imaging at follow-up. These trials totalling 544 enrolled participants were included in the final analyses (see Supplementary data online, Figure S1). The main characteristics of included reports are described in detail in Supplementary data online, Table S1. Briefly, patients with obstructive chronic/stable or unstable coronary artery disease were assigned to PCI with BP-DES (n = 282) or new-generation DP-DES (n = 262) and were scheduled for intravascular imaging with OCT at follow-up. In five trials,5,7,8,19,21 a control OCT of stented coronary segments was required in the setting of pre-specified sub-group analyses; in the remaining trials, the primary endpoints consisted of imaging measures of efficacy. Individuals assigned to PCI with BP-DES received biolimus-eluting stents (BES, Nobori, Terumo Corporation, Japan or Biomatrix Flex, Biosensor Inc., Newport Beach, CA, USA, n = 152) in five trials5,17,18,20,21 or SES (Orsiro, Biotronik, Bülach, Switzerland, Ultimaster, Terumo Corporation, Japan or Itrix, AMG International GmbH, Raesfeld-Borken, Germany, n = 130) in the remaining trials. The overwhelming majority of individuals assigned to a PCI with new-generation DP-DES received everolimus-eluting stents (EES, Xience V/Xience Prime, Abbott Vascular, Santa Clara, CA, USA; Promus/Promus Element, Boston Scientific, Natick, MA, USA, n = 239) whilst ZES (Resolute/Resolute Integrity, Medtronic, Santa Rosa, CA, USA, n = 23) represented the comparator new-generation DP-DES in one trial.6 One trial comprised a third treatment arm of patients receiving fully bioresorbable stents: data belonging to this treatment arm were excluded, as not relevant to the study research question.21 All but three trials,5,20,21 had a multicentre design. Four trials included patients with acute MI.5,6,20,21 Two trials excluded patients with diabetes and comprised a functional assessment of coronary flow at the time of OCT imaging.6,18 One trial restricted the enrolment to patients with successfully treated chronic total occlusions of coronary arteries.8 The definitions and the methodology used to assess outcomes of interest are described in detail in Supplementary data online, Table S2. All interventions were performed in accordance with the standard of care, including stent deployment optimization or use of intravascular imaging at baseline, at the operators’ discretion or according to protocols. Anticoagulation during PCI was accomplished through administration of either unfractionated or low-molecular-weight heparin or bivalirudin in all cases. After coronary interventions, aspirin was recommended indefinitely, whilst thienopyridines were prescribed for a period ranging from ≥6 to 12 months or longer if clinically indicated. All study subjects received standard medical therapies as required. The evaluation of risk of bias among studies is reported in Supplementary data online, Table S3. The main characteristics of patients and lesions treated in the original trials are listed in Table 1. Participants were more often male, with a median age of 62.8 years [interquartile range, 62.2–67.0], and about a fourth were diabetics. Approximately one-third of cases presented with ACS at the time of index PCI. At baseline angiography treated lesions displayed a mean diameter stenosis of 69.5%, a reference vessel diameter of 2.92 mm and a length of 13.3 mm. Approximately 40% of lesions treated had a complex morphology. Table 1 Main baseline features of patients and lesions treated with BP-DES vs. DP-DES among trials included in the study   BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)    BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)  Overall numbers (proportions) and mean values (SD) are reported. N/A, not applicable; ACS, acute coronary syndrome; DS, diameter stenosis; RVD, reference vessel diameter; N/R, not reported; BIOACTIVE, Vascular response after implantation of biolimus A9-eluting stent with bioabsorbable polymer and everolimus-eluting stents with durable polymer; BIOFLOW II, BIOTRONIK-Safety and Clinical PerFormance of the Drug ELuting Orsiro Stent in the Treatment of Subjects With Single de Novo Coronary Artery Lesions—II; CENTURY II, Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease—II; EVERBIO II, Comparison of Everolimus- and Biolimus-Eluting Stents with Everolimus-Eluting Bioresorbable Vascular Scaffold Stents; HATTRICK, Healing at 3 months after percutaneous coronary Intervention for ACS trial; ISAR TEST 6, Intracoronary stenting and angiographic results, Test Safety of Biodegradable and Permanent Limus-Eluting Stents Assessed by Optical Coherence Tomography; NEXT, NOBORI Biolimus-Eluting vs. XIENCE V/PROMUS Everolimus-Eluting Stent Trial; PILOT, Polymer Degrading-Sirolimus Eluting-Coronary Stent Trial; PRISON IV, Hybrid Sirolimus-eluting Stent With Bioresorbable Polymer vs. Everolimus-eluting Stent With Durable Polymer for Total Coronary Occlusions in Native Coronary Arteries; STACCATO, Assessment of stent strut apposition and coverage in coronary arteries with optical coherence tomography in patients with STEMI, NSTEMI and stable/unstable angina undergoing everolimus vs. biolimus A9-eluting stent implantation. a Unstable angina only. Table 1 Main baseline features of patients and lesions treated with BP-DES vs. DP-DES among trials included in the study   BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)    BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)  Overall numbers (proportions) and mean values (SD) are reported. N/A, not applicable; ACS, acute coronary syndrome; DS, diameter stenosis; RVD, reference vessel diameter; N/R, not reported; BIOACTIVE, Vascular response after implantation of biolimus A9-eluting stent with bioabsorbable polymer and everolimus-eluting stents with durable polymer; BIOFLOW II, BIOTRONIK-Safety and Clinical PerFormance of the Drug ELuting Orsiro Stent in the Treatment of Subjects With Single de Novo Coronary Artery Lesions—II; CENTURY II, Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease—II; EVERBIO II, Comparison of Everolimus- and Biolimus-Eluting Stents with Everolimus-Eluting Bioresorbable Vascular Scaffold Stents; HATTRICK, Healing at 3 months after percutaneous coronary Intervention for ACS trial; ISAR TEST 6, Intracoronary stenting and angiographic results, Test Safety of Biodegradable and Permanent Limus-Eluting Stents Assessed by Optical Coherence Tomography; NEXT, NOBORI Biolimus-Eluting vs. XIENCE V/PROMUS Everolimus-Eluting Stent Trial; PILOT, Polymer Degrading-Sirolimus Eluting-Coronary Stent Trial; PRISON IV, Hybrid Sirolimus-eluting Stent With Bioresorbable Polymer vs. Everolimus-eluting Stent With Durable Polymer for Total Coronary Occlusions in Native Coronary Arteries; STACCATO, Assessment of stent strut apposition and coverage in coronary arteries with optical coherence tomography in patients with STEMI, NSTEMI and stable/unstable angina undergoing everolimus vs. biolimus A9-eluting stent implantation. a Unstable angina only. Outcomes Among those originally enrolled, 447 patients (82.1%) with 480 treated lesions had analysable OCT imaging at follow-up. The total number of struts analysed was 118 129 (n = 61 455 and n = 56 674 for lesions treated with BP-DES or new-generation DP-DES, respectively). OCT imaging was performed at a weighted median follow-up of 7 months. Primary outcomes Forest plots for primary outcomes are displayed in Figure 1A and B. NIH thickness, the main primary outcome, was assessed in 436 lesions. Lesions treated with BP-DES showed no difference in terms of NIH thickness as compared to those treated with new-generation DP-DES [range in 64–200 µm vs. 66–156 µm; −11.37 (−29.25, 6.52); P = 0.21]. There was a high heterogeneity for this risk estimate (I2 = 89%). The magnitude of the risk estimate for NIH thickness remained unchanged after the exclusion of the trial6 in which the comparator consisted of lesions treated with new-generation durable-polymer ZES [−11.73 (−30.65, 7.20), P = 0.22; I2 = 90%]. Figure 1 View largeDownload slide Forest plots for primary outcomes with BP-DES vs. new-generation DP-DES. Weighted mean difference for (A) neointima hyperplasia thickness (µm) and odds ratio for (B) lesions with uncovered struts with BP-DES vs. new-generation DP-DES. The diamonds indicate the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. Figure 1 View largeDownload slide Forest plots for primary outcomes with BP-DES vs. new-generation DP-DES. Weighted mean difference for (A) neointima hyperplasia thickness (µm) and odds ratio for (B) lesions with uncovered struts with BP-DES vs. new-generation DP-DES. The diamonds indicate the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. Assessment of struts coverage, the co-primary outcome, was possible for 327 lesions and 279 of these were reported to be uncovered (85.3%). Lesions treated with BP-DES vs. new-generation DP-DES showed a higher risk for any uncovered struts [92.5% vs. 78.4%; 3.50 (1.69–7.26), P = 0.0008; I2 = 0%]. Notably, 90 lesions presented >10% uncovered struts (43.6%, data available for 206 lesions) without a significant difference between BP-DES and new-generation DP-DES [44.1% vs. 43.2%; 1.14 (0.42–3.14), P = 0.80; I2 = 59%]. Secondary outcomes Forest plots for secondary outcomes are displayed in Figure 2A–D. The apposition of stent struts was assessable in 327 lesions and 134 of these were reported to have malapposed struts (40.9%). Lesions treated with BP-DES vs. new-generation DP-DES showed a trend towards higher risk for any malapposed struts [48.1% vs. 34.1%; 2.01 (0.98–4.12), P = 0.06; I2 = 42%]. The mean percentage of malapposed struts (data available for 370 lesions) was significantly higher with BP-DES vs. new-generation DP-DES [range 0.48–4.2 vs. 0.2–4.3; 0.65 (0.12, 1.17); P = 0.02; I2 = 4%]. Notably, 21 lesions presented >5% malapposed struts (12.6%, data available for 166 lesions) without a significant difference between BP-DES and new-generation DP-DES [12.5% vs. 12.7%; 0.94 (0.13–6.70), P = 0.95; I2 = 66%]. Figure 2 View largeDownload slide Forest plots for secondary outcomes with BP-DES vs. new-generation DP-DES. Odds ratios for (A) lesions with malapposed struts and (D) target lesion/vessel revascularization weighted mean difference for (B) neointima hyperplasia area (mm2) (C) neointima hyperplasia volume (mm3), with BP-DES vs. new-generation DP-DES. The diamonds indicates the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. Figure 2 View largeDownload slide Forest plots for secondary outcomes with BP-DES vs. new-generation DP-DES. Odds ratios for (A) lesions with malapposed struts and (D) target lesion/vessel revascularization weighted mean difference for (B) neointima hyperplasia area (mm2) (C) neointima hyperplasia volume (mm3), with BP-DES vs. new-generation DP-DES. The diamonds indicates the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. NIH area was assessed in 426 lesions. Lesions treated with BP-DES showed less NIH area as compared to those treated with new-generation DP-DES [range 0.38–1.31 mm2 vs. 0.52–1.56 mm2; −0.12 (−0.24, −0.00), P = 0.046; I2 = 55%]. NIH volume was assessed in 266 lesions. Lesions treated with BP-DES showed no difference in terms of NIH volume as compared to those treated with new-generation DP-DES [range 7–17.7 mm3 vs. 8.4–16.5 mm3; 0.26 (−3.21, 3.74), P = 0.19; I2 = 27%]. Notably, the proportion of lesions available for risk estimation of this outcome was the lowest, accounting for 55.4% of those with analysable OCT imaging at follow-up included in this report. TLR/TVR occurred in 25 patients [7.1%, data available for 360 (80.5%) patients enrolled in seven studies5,7,8,16–18,20]. Patients treated with BP-DES displayed a risk of TLR/TVR comparable to that of patients treated with new-generation DP-DES [7.4% vs. 6.5%; 1.16 (0.51–2.65), P = 0.73; I2 = 0%, phet = 0.90]. Notably, the proportion of OCT-driven TLRs/TVRs was comparable between treatment groups (46.1% and 41.6% for BP-DES and new-generation DP-DES, respectively). Small study effects, influence, and subgroup analyses The funnel plot for NIH thickness is presented in Supplementary data online, Figure S2A. We found no evidence for small study effects, neither by visual inspection of funnel plots or by asymmetry test. The influence analysis demonstrated that no single study significantly altered the direction of the summary OR for NIH thickness (see Supplementary data online, Figure S2B). Finally, the subgroup analysis displayed that the time-point of OCT imaging [P for interaction (pint) = 0.31], the antiproliferative drug eluted from biodegradable-polymer stent platforms (pint = 0.09), the number of participants in each included trial (pint = 0.73), the inclusion of patients with diabetes (pint = 0.69) or acute MI (pint = 0.50) were not associated with estimated OR for NIH thickness. Conversely, the strut thickness of BP-DES displayed a significant interaction with the treatment effect for the primary outcome (pint = 0.043, see Supplementary data online, Figure S3). Indeed, lesions treated with thick-struts (>100 μm) BP-DES were associated with less NIH thickness as compared with those treated with new-generation DP-DES [−20.39 (−33.83, −6.95), P = 0.003; I2 = 39%]. Discussion This meta-analysis aggregated the study-level data of 10 trials in which OCT imaging at follow-up served to assess the vascular response to PCI with BP-DES vs. new-generation DP-DES. The main findings of this report can be summarized as follows: (i) OCT performed at a median follow-up of 7 months displays decreased neointima growth and higher risk for uncovered struts after implantation of thick-struts BP-DES in comparison to new-generation DP-DES; (ii) overall, BP-DES are associated with higher incidence of malapposed struts as compared with new-generation DP-DES. BP-DES with polylactide-based carriers were developed to overcome the biological shortcomings of early-generation DP-DES.22 Indeed, initial OCT-based studies documented significantly improved healing with BP-DES vs. early-generation DP-DES.23 More recently, however, OCT studies of BP-DES vs. new-generation DP-DES led to disappointing results,5,24 questioning the role of BP-DES technology with respect to new-generation, more biocompatible DP-DES. Of note, BP-DES technology has recently evolved toward thinner metallic backbones and several new platforms received CE-mark approval, due to favourable comparative efficacy and safety data against new-generation DP-DES.25,26 This study analysed the largest population of PCI-patients assigned to BP-DES or new-generation DP-DES with OCT imaging follow-up data. Despite overall BP-DES and new-generation DP-DES displayed comparable NIH thickness at 7-month OCT imaging, there was a high heterogeneity for this risk estimate. Indeed, the subgroup analysis found that thick-struts but not thin-strut BP-DES had less NIH thickness as compared with new-generation DP-DES. Notably, the comparable risk for TLR/TVR between patients treated with BP-DES and those treated with new-generation DP-DES rules-out an artificial underestimation of NIH thickness dependent on higher rates of revascularization of the new-generation DP-DES group.27 This analysis confirms that thin-struts stents allow for accelerated endothelial recovery, faster integration into the vessel wall and complete re-endothelialization in comparison with thick-struts platforms.28 In addition, our results corroborate the OCT-findings of the Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) VII trial, which randomly assigned moderately complex lesions to PCI with thick-struts vs. thin-struts BP-DES.29 This imaging-based sub-analysis found a more heterogeneous healing pattern and increased proportion of treated-lesions presenting <90% of strut coverage after implantation of thick-struts as compared to thin-struts BP-DES,30 lending support to a device-specific healing process among biodegradable-polymer drug-eluting stent platforms. Lesions treated with BP-DES presented a greater prevalence of uncovered struts as compared to those treated with new-generation DP-DES. Notably, only one8 out of six trials available for this risk estimate studied thin-struts BP-DES vs. new-generation DP-DES. The clinical impact of OCT-detected incomplete strut coverage remains unknown, though a ratio of uncovered to all struts >30% in 2–3 mm long in-stent sections have been associated with thrombotic coronary occlusions in a histopathological study.31 Despite previous observations found a higher thrombotic risk within 1 year with thick-strut BP-DES as compared to new-generation DP-DES3 and thin-strut BP-DES,29 the paucity of clinical data available in this report precluded assessing whether the impaired coverage observed with thick-strut BP-DES led to worse outcomes as compared with new-generation DP-DES. Lesions treated with BP-DES showed a tendency towards an increased risk for malapposition in comparison with those treated with new-generation DP-DES. The lack of OCT imaging at baseline precludes a distinction between incomplete strut apposition at time of index intervention and acquired malapposition occurring late after implementation of BP-DES. For instance, two studies8,30 have described clusters of malapposed struts and aneurysmatic coronary segments after PCI with thin-struts biodegradable-polymer stent platforms eluting sirolimus, challenging the common perception that aneurysm formation is almost absent with new-generation drug-eluting stent platforms.32 The relative contribution to stent coverage and apposition of different antiproliferative drugs and doses, variable absorption kinetics of coatings and mechanical properties of underlying stent backbones remains unclear and our report highlights once more that performance of DES depends on a complex interplay between all these components. For example, we are unable to decipher whether the increased risk for malapposition observed after PCI with BP-DES vs. new-generation DP-DES was due to vascular toxicity of eluted drug, as observed with early-generation SES,32 or to a transient inflammation owing to sustained degradation process of certain biodegradable polymer formulations investigated in this report.33 Finally, this analysis reaffirms the excellent healing profile of contemporary DP-DES, especially of those with a fluoro-passivated permanent polymer coating, which constituted the majority of the implants in the comparator group analysed in this study. Imaging data in preclinical models support the favourable healing properties of fluoropolymer-based EES as compared to BP-DES either with thick- or thin-strut backbone designs.34 The fluoro-passivation of the durable polymer coating35 in conjunction with the high antiproliferative effect of everolimus36 and a thin-strut platform likely contribute to the same extent for the unprecedented safety and efficacy of these implants as compared with other stent platforms. In this respect, these devices should be further regarded as a benchmark for future comparative studies of vascular healing after coronary stenting. Study limitations The current study has a number of limitations. First, this is a study-level meta-analysis and shares the limitations of such a kind of analyses. In this specific case, despite tougher, a meta-analysis based on individual patient- and lesion-data would have been of help to disclose whether polymers, strut thickness and antiproliferative drugs have a different impact on vascular response. Amongst others, in the absence of lesion-based data comparative analyses of healing profiles belonging to different platforms should be interpreted with caution as differences in implantation techniques could significantly influence imaging results. Second, we focused on a limited number of drug-eluting stent technologies and current results do not apply to other platforms that are not included in this analysis. Finally, OCT imaging data was mostly acquired in well-selected patients and lesions and after a median follow-up of 7 months. In this respect, the findings and the magnitude of the treatment effects observed in the present analysis are neither generalizable to higher-risk subsets of patients nor applicable to a time-point different from that available here. Conclusions In PCI-patients with available OCT imaging at follow-up, BP-DES with thicker backbones delays vascular response as compared with new-generation DP-DES. The higher risk for strut malapposition observed with BP-DES vs. new-generation DP-DES represents an important finding, which requires further investigation. Dedicated randomized trials powered for clinical endpoints are mandatory to address potential clinical sequelae of such imaging data. Supplementary data Supplementary data are available at European Heart Journal – Cardiovascular Imaging online. Conflict of interest: R.C. reports support from the Irish Board for Training in Cardiovascular Medicine sponsored by MSD. D.G. and N.M. are the recipients of a research fellowship grant funded by European Association of Percutaneous Cardiovascular Interventions (EAPCI). R.A.B. reports receiving lecture fees from B. Braun Melsungen AG, Biotronik, and Boston Scientific and research grants to the institution from Boston Scientific and Heartflow, outside the submitted work. A.K. reports holding patents related to drug-eluting stent technology, outside the submitted work. M.J. reports personal fees from Orbus Neich, grants and personal fees from Biotronik, personal fees from Coramaze, personal fees from Astra Zeneca, personal fees from Bristol-Myers-Squibb, outside the submitted work. The other authors declare no potential conflict of interest. References 1 Byrne RA, Kastrati A. No country for old stents? Improving long-term patient outcomes with biodegradable polymer drug-eluting stents. 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The hazards of scoring the quality of clinical trials for meta-analysis. JAMA  1999; 282: 1054– 60. http://dx.doi.org/10.1001/jama.282.11.1054 Google Scholar CrossRef Search ADS PubMed  13 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ  2003; 327: 557– 60. http://dx.doi.org/10.1136/bmj.327.7414.557 Google Scholar CrossRef Search ADS PubMed  14 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ  1997; 315: 629– 34. http://dx.doi.org/10.1136/bmj.315.7109.629 Google Scholar CrossRef Search ADS PubMed  15 Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med  2009; 6: 264– 9. Google Scholar CrossRef Search ADS   16 Tada T, Byrne RA, Schuster T, Cuni R, Kitabata H, Tiroch K et al.   Early vascular healing with rapid breakdown biodegradable polymer sirolimus-eluting versus durable polymer everolimus-eluting stents assessed by optical coherence tomography. Cardiovasc Revasc Med  2013; 14: 84– 9. Google Scholar CrossRef Search ADS PubMed  17 Tada T, Kastrati A, Byrne RA, Schuster T, Cuni R, King LA et al.   Randomized comparison of biolimus-eluting stents with biodegradable polymer versus everolimus-eluting stents with permanent polymer coatings assessed by optical coherence tomography. Int J Cardiovasc Imaging  2014; 30: 495– 504. Google Scholar CrossRef Search ADS PubMed  18 Chamié D, Almeida BO, Grandi F, Filho EM, Ribamar Costa JJ, Costa R et al.   Vascular response after implantation of biolimus A9-eluting stent with bioabsorbable polymer and everolimus-eluting stents with durable polymer. Results of the optical coherence tomography analysis of the BIOACTIVE randomized trial. Rev Bras Cardiol Invasiva  2015; 23: 28– 37. Google Scholar CrossRef Search ADS   19 Windecker S, Haude M, Neumann FJ, Stangl K, Witzenbichler B, Slagboom T et al.   Comparison of a novel biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent: results of the randomized BIOFLOW-II trial. Circ Cardiovasc Interv  2015; 8: e001441. Google Scholar CrossRef Search ADS PubMed  20 Adriaenssens T, Ughi GJ, Dubois C, De Cock D, Onsea K, Bennett J et al.   STACCATO (assessment of stent strut apposition and coverage in coronary arteries with optical coherence tomography in patients with STEMI, NSTEMI and stable/unstable angina undergoing everolimus vs. biolimus A9-eluting stent implantation): a randomised controlled trial. EuroIntervention  2016; 11: e1619– 26. 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Google Scholar CrossRef Search ADS PubMed  30 Andreasen LN, Holm NR, Balleby IR, Krusell LR, Maeng M, Jakobsen L et al.   Randomized comparison of sirolimus eluting, and biolimus eluting bioresorbable polymer stents: the SORT-OUT VII optical coherence tomography study. Eur Heart J Cardiovasc Imaging  2017. 31 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  32 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. 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Google Scholar CrossRef Search ADS PubMed  36 Steigerwald K, Ballke S, Quee SC, Byrne RA, Vorpahl M, Vogeser M et al.   Vascular healing in drug-eluting stents: differential drug-associated response of limus-eluting stents in a preclinical model of stent implantation. EuroIntervention  2012; 8: 752– 9. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Vascular response to percutaneous coronary intervention with biodegradable-polymer vs. new-generation durable-polymer drug-eluting stents: a meta-analysis of optical coherence tomography imaging trials

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Abstract

Abstract Aims Whether biodegradable-polymer drug-eluting stents (BP-DES) induce a vascular response at follow-up more favourable than that of new-generation durable-polymer drug-eluting stents (DP-DES) remains controversial. We sought to evaluate the vascular response to percutaneous coronary intervention (PCI) with BP-DES vs. new-generation DP-DES as assessed by optical coherence tomography (OCT) imaging at follow-up. Methods and results We undertook a meta-analysis of aggregate data by searching electronic scientific databases for investigations of PCI-patients receiving BP-DES vs. new-generation DP-DES and OCT imaging at follow-up. The primary outcome was neointima hyperplasia (NIH) thickness. The co-primary outcome was the incidence of lesions with uncovered struts. The main secondary outcome was the incidence of lesions with malapposed struts. Among 10 trials, a total of 544 PCI-patients were assigned to BP-DES (n = 282) or new-generation DP-DES (n = 262). Of these, 447 participants with 480 treated lesions had analysable OCT imaging at a weighted median follow-up of 7 months. Lesions treated with BP-DES vs. new-generation DP-DES showed comparable NIH thickness [weighted mean difference 95% confidence intervals (CI)  = −11.37 (−29.25, 6.52); P = 0.21]. However, thick-struts (>100 μm) BP-DES showed less NIH thickness as compared to new-generation DP-DES [−20.39 (−33.83, −6.95); P = 0.003]. BP-DES vs. new-generation DP-DES showed a higher risk for uncovered struts [odds ratio 95% CI = 3.50 (1.69–7.26); P = 0.0008] and a trend towards higher risk for malapposed struts [2.01 (0.98–4.12); P = 0.06]. Conclusion In PCI-patients with available OCT imaging at follow-up, BP-DES with thicker backbones delay vascular response as compared with new-generation DP-DES. biodegradable polymer, drug-eluting stent, durable polymer, meta-analysis, optical coherence tomography, percutaneous coronary intervention Introduction The peculiarity of biodegradable-polymer drug-eluting stents (BP-DES) is that once the anti-restenotic drug is eluted and the carrier completely degraded, the stent platform left behind resembles that of a bare metal stent. By virtue of the transient nature of the carrier, these modern devices for percutaneous coronary intervention (PCI) should elicit a more physiological vascular response in comparison to durable-polymer drug-eluting stents (DP-DES).1 Previous clinical investigations found improved healing and lower thrombogenicity with BP-DES compared to early-generation DP-DES.2 However, the favourable vascular behaviour of BP-DES was not confirmed in comparisons against new-generation DP-DES.3 Optical coherence tomography (OCT) is an innovative tool for high-resolution intravascular imaging. By providing near histology-level images, OCT has been used to unravel the coronary response following stenting.4 Since difference in stent platform, biocompatibility, and degradation kinetics of polymers may impact the healing patterns of stented coronary segments and the inherent risk for adverse outcomes, investigations of vascular response after PCI with BP-DES vs. new-generation DP-DES may be a matter of clinical interest. In light of inconsistent results of recent imaging studies dealing with this topic,5–8 we performed a meta-analysis of trials evaluating the vascular response after PCI with BP-DES or new-generation DP-DES, as measured by OCT imaging at follow-up. Methods Search strategy and selection criteria We searched Medline, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), scientific sessions abstracts, and relevant websites (www.cardiosource.com, www.clinicaltrialresults.org, www.escardio.org, www.tctmd.com, www.theheart.org) for investigations of PCI-patients assigned to BP-DES or new-generation DP-DES and OCT imaging at follow-up. The reference lists from two previous meta-analyses9,10 evaluating vascular response with OCT after coronary stenting were checked to identify further citations. For this report, stent platforms other than early-generation sirolimus-eluting stents (SES/Cypher, Cordis, Warren, NJ, USA), paclitaxel-eluting stents (Taxus, Boston Scientific, Natick, MA, USA) and fast-release zotarolimus-eluting stents (ZES/Endeavor, Medtronic, Santa Rosa, CA, USA) were considered new-generation DP-DES. Search terms included the keywords and the corresponding Medical Subject Headings for: ‘drug-eluting stent(s)’, ‘biodegradable polymer’, ‘durable polymer’, ‘OCT’, ‘trial’, and ‘randomized trial’. No restrictions concerning language or publication status were imposed. Inclusion criteria were (i): OCT imaging performed between ≥1 and 12 months after BP-DES or new-generation DP-DES implantation; and (ii) description of OCT imaging protocols. Comparisons other than BP-DES vs. new-generation DP-DES were ineligible. We performed the last search of scientific databases for articles dealing with the topic under investigation on 17 May 2017. The reference lists from all eligible studies were checked to identify further citations. Data collection and assessment of risk of bias Two investigators (SC and EX) independently assessed publications for eligibility at the title and/or abstract level. Divergences were resolved by consensus. Studies that met inclusion criteria were selected for further analysis. Risk of bias was independently evaluated for each study by the same two investigators in accordance with The Cochrane Collaboration method.11 Composite quality scores were not assigned.12 Outcomes The primary outcome of the current report was neointima hyperplasia (NIH) thickness and the co-primary outcome was the incidence of lesions with uncovered struts. The main secondary outcome was the incidence of lesions with malapposed struts. Other secondary outcomes of interest were NIH area, NIH volume and target lesion/vessel revascularization (TLR/TVR). All endpoints were evaluated in accordance with intention-to-treat principle and definitions reported in the original protocols. Statistical analysis Odds ratio and the weighted mean difference with 95% confidence intervals were used to compare the outcomes of interest between BP-DES and new-generation DP-DES and pooled using the Mantel–Haenszel random-effect model (DerSimonian and Laird). Heterogeneity between trials was quantified using the I2 statistic accompanied by a χ2 test: I2 values around 25%, 50%, and 75% were suggested to indicate low, moderate, or high heterogeneity, respectively.13 In addition, we estimated the between-study variance (τ2). The possibility of small study effects resulting from publication bias or other biases was examined for main primary outcome by means of visual inspection of funnel plots of the ORs of individual trials against their standard errors, accompanied by a statistical test of asymmetry.14 An influence analysis, in which meta-analysis estimates are computed omitting one study at a time, was performed for the risk estimation of main primary outcome. Using a χ2 test for subgroup by treatment interaction, we determined whether certain covariates were associated with risk estimation for the main primary outcome. The covariates investigated were: the time-point of OCT imaging (≤6 months vs. >6 months after index PCI), the strut thickness (≤100 μm vs. >100 μm) or the antiproliferative drug (sirolimus vs. biolimus) of BP-DES platforms, the minimum number of participants in each included trial (≤40 patients vs. >40 patients), and the inclusion of patients with diabetes (yes vs. no) or acute MI (yes vs. no). This study was reported in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement (see Supplementary data online).15 All analyses were performed in RevMan (Review Manager, Version 5.3, The Cochrane Collaboration, Copenhagen, Denmark) and R (version 3.3.2; R Foundation for Statistical Computing, Vienna, Austria). This study is registered with PROSPERO, number CRD42017067525. Results The electronic search identified 10 studies, all with full-length articles,5–8,16–21 in which PCI-patients were assigned to BP-DES or new-generation DP-DES and subsequent OCT imaging at follow-up. These trials totalling 544 enrolled participants were included in the final analyses (see Supplementary data online, Figure S1). The main characteristics of included reports are described in detail in Supplementary data online, Table S1. Briefly, patients with obstructive chronic/stable or unstable coronary artery disease were assigned to PCI with BP-DES (n = 282) or new-generation DP-DES (n = 262) and were scheduled for intravascular imaging with OCT at follow-up. In five trials,5,7,8,19,21 a control OCT of stented coronary segments was required in the setting of pre-specified sub-group analyses; in the remaining trials, the primary endpoints consisted of imaging measures of efficacy. Individuals assigned to PCI with BP-DES received biolimus-eluting stents (BES, Nobori, Terumo Corporation, Japan or Biomatrix Flex, Biosensor Inc., Newport Beach, CA, USA, n = 152) in five trials5,17,18,20,21 or SES (Orsiro, Biotronik, Bülach, Switzerland, Ultimaster, Terumo Corporation, Japan or Itrix, AMG International GmbH, Raesfeld-Borken, Germany, n = 130) in the remaining trials. The overwhelming majority of individuals assigned to a PCI with new-generation DP-DES received everolimus-eluting stents (EES, Xience V/Xience Prime, Abbott Vascular, Santa Clara, CA, USA; Promus/Promus Element, Boston Scientific, Natick, MA, USA, n = 239) whilst ZES (Resolute/Resolute Integrity, Medtronic, Santa Rosa, CA, USA, n = 23) represented the comparator new-generation DP-DES in one trial.6 One trial comprised a third treatment arm of patients receiving fully bioresorbable stents: data belonging to this treatment arm were excluded, as not relevant to the study research question.21 All but three trials,5,20,21 had a multicentre design. Four trials included patients with acute MI.5,6,20,21 Two trials excluded patients with diabetes and comprised a functional assessment of coronary flow at the time of OCT imaging.6,18 One trial restricted the enrolment to patients with successfully treated chronic total occlusions of coronary arteries.8 The definitions and the methodology used to assess outcomes of interest are described in detail in Supplementary data online, Table S2. All interventions were performed in accordance with the standard of care, including stent deployment optimization or use of intravascular imaging at baseline, at the operators’ discretion or according to protocols. Anticoagulation during PCI was accomplished through administration of either unfractionated or low-molecular-weight heparin or bivalirudin in all cases. After coronary interventions, aspirin was recommended indefinitely, whilst thienopyridines were prescribed for a period ranging from ≥6 to 12 months or longer if clinically indicated. All study subjects received standard medical therapies as required. The evaluation of risk of bias among studies is reported in Supplementary data online, Table S3. The main characteristics of patients and lesions treated in the original trials are listed in Table 1. Participants were more often male, with a median age of 62.8 years [interquartile range, 62.2–67.0], and about a fourth were diabetics. Approximately one-third of cases presented with ACS at the time of index PCI. At baseline angiography treated lesions displayed a mean diameter stenosis of 69.5%, a reference vessel diameter of 2.92 mm and a length of 13.3 mm. Approximately 40% of lesions treated had a complex morphology. Table 1 Main baseline features of patients and lesions treated with BP-DES vs. DP-DES among trials included in the study   BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)    BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)  Overall numbers (proportions) and mean values (SD) are reported. N/A, not applicable; ACS, acute coronary syndrome; DS, diameter stenosis; RVD, reference vessel diameter; N/R, not reported; BIOACTIVE, Vascular response after implantation of biolimus A9-eluting stent with bioabsorbable polymer and everolimus-eluting stents with durable polymer; BIOFLOW II, BIOTRONIK-Safety and Clinical PerFormance of the Drug ELuting Orsiro Stent in the Treatment of Subjects With Single de Novo Coronary Artery Lesions—II; CENTURY II, Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease—II; EVERBIO II, Comparison of Everolimus- and Biolimus-Eluting Stents with Everolimus-Eluting Bioresorbable Vascular Scaffold Stents; HATTRICK, Healing at 3 months after percutaneous coronary Intervention for ACS trial; ISAR TEST 6, Intracoronary stenting and angiographic results, Test Safety of Biodegradable and Permanent Limus-Eluting Stents Assessed by Optical Coherence Tomography; NEXT, NOBORI Biolimus-Eluting vs. XIENCE V/PROMUS Everolimus-Eluting Stent Trial; PILOT, Polymer Degrading-Sirolimus Eluting-Coronary Stent Trial; PRISON IV, Hybrid Sirolimus-eluting Stent With Bioresorbable Polymer vs. Everolimus-eluting Stent With Durable Polymer for Total Coronary Occlusions in Native Coronary Arteries; STACCATO, Assessment of stent strut apposition and coverage in coronary arteries with optical coherence tomography in patients with STEMI, NSTEMI and stable/unstable angina undergoing everolimus vs. biolimus A9-eluting stent implantation. a Unstable angina only. Table 1 Main baseline features of patients and lesions treated with BP-DES vs. DP-DES among trials included in the study   BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)    BIOACTIVE  BIOFLOW II  CENTURY II  EVERBIO II  HATTRICK  ISAR TEST 6  NEXT  PILOT  PRISON IV  STACCATO  Patients  40  65  36  47  46  34  121  20  71  64  Age (years)  58.6 (7.6)  63.1 (10.1)  73.1 (8.1)  67.0 (8.5)  62.2 (10.9)  67.8 (9.6)  67.0 (8.5)  62.6 (11.5)  62.6 (13.4)  62.2 (9.5)  Male gender  13/26 (50.0)  55 (84.6)  20/27 (74.1)  39/46 (84.7)  35/44 (79.5)  29 (85.2)  70/91 (76.9)  18 (90.0)  44/60 (73.3)  51 (79.6)  Diabetes  N/A  11 (16.9)  9/27 (33.3)  14/46 (30.4)  N/A  10 (29.4)  37/91 (40.6)  4 (20.0)  12/60 (20.0)  8 (12.5)  ACS at admission  3/26 (11.5)a  N/A  0 (-)  20/46 (43.4)  44/44 (100)  11 (32.3)  13/91 (14.2)  3 (15.0)a  0 (-)  42 (65.6)  Lesions  26  55  28  52  44  41  106  20  60  64  DS (%)  68.2 (12.6)  N/R  76.8 (12.7)  81.0 (17.0)  N/R  63.0 (12.2)  69.5 (14.5)  65.4 (9.7)  100  N/R  RVD (mm)  2.97 (0.37)  N/R  2.92 (0.41)  2.61 (0.89)  N/R  2.85 (0.47)  2.65 (0.56)  2.92 (0.43)  N/R  3.05 (0.55)  Length (mm)  10.5 (4.52)  N/R  19.0 (8.9)  N/R  N/R  11.3 (5.6)  N/R  12.6 (3.3)  N/R  14.0 (6.2)  Type B2/C  11 (42.3)  N/R  11 (39.2)  N/R  N/R  26/41 (65.0)  N/R  7 (35.5)  100  N/R  Predilation   BP-DES  5/15 (33.3)  N/R  N/R  20/26 (76.9)  17/22 (77.3)  15/19 (82.3)  N/R  N/R  N/R  20/32 (62.5)   DP-DES  5/11 (45.4)      23/26 (88.4)  19/22 (82.6)  18/22 (81.8)        21/32 (65.6)  Postdilation   BP-DES  14/15 (93.3)  N/R  6/13 (46.1)  12/26 (46.1)  9/22 (40.9)  N/R  33/51 (64.7)  N/R  6/30 (20.0)  16/32 (50.0)   DP-DES  10/11 (90.9)    5/15 (33.3)  8/26 (30.7)  18/22 (78.3)    36/55 (65.4)    7/30 (23.3)  7/32 (21.8)  Overall numbers (proportions) and mean values (SD) are reported. N/A, not applicable; ACS, acute coronary syndrome; DS, diameter stenosis; RVD, reference vessel diameter; N/R, not reported; BIOACTIVE, Vascular response after implantation of biolimus A9-eluting stent with bioabsorbable polymer and everolimus-eluting stents with durable polymer; BIOFLOW II, BIOTRONIK-Safety and Clinical PerFormance of the Drug ELuting Orsiro Stent in the Treatment of Subjects With Single de Novo Coronary Artery Lesions—II; CENTURY II, Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease—II; EVERBIO II, Comparison of Everolimus- and Biolimus-Eluting Stents with Everolimus-Eluting Bioresorbable Vascular Scaffold Stents; HATTRICK, Healing at 3 months after percutaneous coronary Intervention for ACS trial; ISAR TEST 6, Intracoronary stenting and angiographic results, Test Safety of Biodegradable and Permanent Limus-Eluting Stents Assessed by Optical Coherence Tomography; NEXT, NOBORI Biolimus-Eluting vs. XIENCE V/PROMUS Everolimus-Eluting Stent Trial; PILOT, Polymer Degrading-Sirolimus Eluting-Coronary Stent Trial; PRISON IV, Hybrid Sirolimus-eluting Stent With Bioresorbable Polymer vs. Everolimus-eluting Stent With Durable Polymer for Total Coronary Occlusions in Native Coronary Arteries; STACCATO, Assessment of stent strut apposition and coverage in coronary arteries with optical coherence tomography in patients with STEMI, NSTEMI and stable/unstable angina undergoing everolimus vs. biolimus A9-eluting stent implantation. a Unstable angina only. Outcomes Among those originally enrolled, 447 patients (82.1%) with 480 treated lesions had analysable OCT imaging at follow-up. The total number of struts analysed was 118 129 (n = 61 455 and n = 56 674 for lesions treated with BP-DES or new-generation DP-DES, respectively). OCT imaging was performed at a weighted median follow-up of 7 months. Primary outcomes Forest plots for primary outcomes are displayed in Figure 1A and B. NIH thickness, the main primary outcome, was assessed in 436 lesions. Lesions treated with BP-DES showed no difference in terms of NIH thickness as compared to those treated with new-generation DP-DES [range in 64–200 µm vs. 66–156 µm; −11.37 (−29.25, 6.52); P = 0.21]. There was a high heterogeneity for this risk estimate (I2 = 89%). The magnitude of the risk estimate for NIH thickness remained unchanged after the exclusion of the trial6 in which the comparator consisted of lesions treated with new-generation durable-polymer ZES [−11.73 (−30.65, 7.20), P = 0.22; I2 = 90%]. Figure 1 View largeDownload slide Forest plots for primary outcomes with BP-DES vs. new-generation DP-DES. Weighted mean difference for (A) neointima hyperplasia thickness (µm) and odds ratio for (B) lesions with uncovered struts with BP-DES vs. new-generation DP-DES. The diamonds indicate the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. Figure 1 View largeDownload slide Forest plots for primary outcomes with BP-DES vs. new-generation DP-DES. Weighted mean difference for (A) neointima hyperplasia thickness (µm) and odds ratio for (B) lesions with uncovered struts with BP-DES vs. new-generation DP-DES. The diamonds indicate the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. Assessment of struts coverage, the co-primary outcome, was possible for 327 lesions and 279 of these were reported to be uncovered (85.3%). Lesions treated with BP-DES vs. new-generation DP-DES showed a higher risk for any uncovered struts [92.5% vs. 78.4%; 3.50 (1.69–7.26), P = 0.0008; I2 = 0%]. Notably, 90 lesions presented >10% uncovered struts (43.6%, data available for 206 lesions) without a significant difference between BP-DES and new-generation DP-DES [44.1% vs. 43.2%; 1.14 (0.42–3.14), P = 0.80; I2 = 59%]. Secondary outcomes Forest plots for secondary outcomes are displayed in Figure 2A–D. The apposition of stent struts was assessable in 327 lesions and 134 of these were reported to have malapposed struts (40.9%). Lesions treated with BP-DES vs. new-generation DP-DES showed a trend towards higher risk for any malapposed struts [48.1% vs. 34.1%; 2.01 (0.98–4.12), P = 0.06; I2 = 42%]. The mean percentage of malapposed struts (data available for 370 lesions) was significantly higher with BP-DES vs. new-generation DP-DES [range 0.48–4.2 vs. 0.2–4.3; 0.65 (0.12, 1.17); P = 0.02; I2 = 4%]. Notably, 21 lesions presented >5% malapposed struts (12.6%, data available for 166 lesions) without a significant difference between BP-DES and new-generation DP-DES [12.5% vs. 12.7%; 0.94 (0.13–6.70), P = 0.95; I2 = 66%]. Figure 2 View largeDownload slide Forest plots for secondary outcomes with BP-DES vs. new-generation DP-DES. Odds ratios for (A) lesions with malapposed struts and (D) target lesion/vessel revascularization weighted mean difference for (B) neointima hyperplasia area (mm2) (C) neointima hyperplasia volume (mm3), with BP-DES vs. new-generation DP-DES. The diamonds indicates the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. Figure 2 View largeDownload slide Forest plots for secondary outcomes with BP-DES vs. new-generation DP-DES. Odds ratios for (A) lesions with malapposed struts and (D) target lesion/vessel revascularization weighted mean difference for (B) neointima hyperplasia area (mm2) (C) neointima hyperplasia volume (mm3), with BP-DES vs. new-generation DP-DES. The diamonds indicates the point estimate and the left and the right ends of the lines the (95% CI). BP-DES, biodegradable-polymer drug-eluting stents; DP-DES, durable-polymer drug-eluting stents; CI, confidence intervals. NIH area was assessed in 426 lesions. Lesions treated with BP-DES showed less NIH area as compared to those treated with new-generation DP-DES [range 0.38–1.31 mm2 vs. 0.52–1.56 mm2; −0.12 (−0.24, −0.00), P = 0.046; I2 = 55%]. NIH volume was assessed in 266 lesions. Lesions treated with BP-DES showed no difference in terms of NIH volume as compared to those treated with new-generation DP-DES [range 7–17.7 mm3 vs. 8.4–16.5 mm3; 0.26 (−3.21, 3.74), P = 0.19; I2 = 27%]. Notably, the proportion of lesions available for risk estimation of this outcome was the lowest, accounting for 55.4% of those with analysable OCT imaging at follow-up included in this report. TLR/TVR occurred in 25 patients [7.1%, data available for 360 (80.5%) patients enrolled in seven studies5,7,8,16–18,20]. Patients treated with BP-DES displayed a risk of TLR/TVR comparable to that of patients treated with new-generation DP-DES [7.4% vs. 6.5%; 1.16 (0.51–2.65), P = 0.73; I2 = 0%, phet = 0.90]. Notably, the proportion of OCT-driven TLRs/TVRs was comparable between treatment groups (46.1% and 41.6% for BP-DES and new-generation DP-DES, respectively). Small study effects, influence, and subgroup analyses The funnel plot for NIH thickness is presented in Supplementary data online, Figure S2A. We found no evidence for small study effects, neither by visual inspection of funnel plots or by asymmetry test. The influence analysis demonstrated that no single study significantly altered the direction of the summary OR for NIH thickness (see Supplementary data online, Figure S2B). Finally, the subgroup analysis displayed that the time-point of OCT imaging [P for interaction (pint) = 0.31], the antiproliferative drug eluted from biodegradable-polymer stent platforms (pint = 0.09), the number of participants in each included trial (pint = 0.73), the inclusion of patients with diabetes (pint = 0.69) or acute MI (pint = 0.50) were not associated with estimated OR for NIH thickness. Conversely, the strut thickness of BP-DES displayed a significant interaction with the treatment effect for the primary outcome (pint = 0.043, see Supplementary data online, Figure S3). Indeed, lesions treated with thick-struts (>100 μm) BP-DES were associated with less NIH thickness as compared with those treated with new-generation DP-DES [−20.39 (−33.83, −6.95), P = 0.003; I2 = 39%]. Discussion This meta-analysis aggregated the study-level data of 10 trials in which OCT imaging at follow-up served to assess the vascular response to PCI with BP-DES vs. new-generation DP-DES. The main findings of this report can be summarized as follows: (i) OCT performed at a median follow-up of 7 months displays decreased neointima growth and higher risk for uncovered struts after implantation of thick-struts BP-DES in comparison to new-generation DP-DES; (ii) overall, BP-DES are associated with higher incidence of malapposed struts as compared with new-generation DP-DES. BP-DES with polylactide-based carriers were developed to overcome the biological shortcomings of early-generation DP-DES.22 Indeed, initial OCT-based studies documented significantly improved healing with BP-DES vs. early-generation DP-DES.23 More recently, however, OCT studies of BP-DES vs. new-generation DP-DES led to disappointing results,5,24 questioning the role of BP-DES technology with respect to new-generation, more biocompatible DP-DES. Of note, BP-DES technology has recently evolved toward thinner metallic backbones and several new platforms received CE-mark approval, due to favourable comparative efficacy and safety data against new-generation DP-DES.25,26 This study analysed the largest population of PCI-patients assigned to BP-DES or new-generation DP-DES with OCT imaging follow-up data. Despite overall BP-DES and new-generation DP-DES displayed comparable NIH thickness at 7-month OCT imaging, there was a high heterogeneity for this risk estimate. Indeed, the subgroup analysis found that thick-struts but not thin-strut BP-DES had less NIH thickness as compared with new-generation DP-DES. Notably, the comparable risk for TLR/TVR between patients treated with BP-DES and those treated with new-generation DP-DES rules-out an artificial underestimation of NIH thickness dependent on higher rates of revascularization of the new-generation DP-DES group.27 This analysis confirms that thin-struts stents allow for accelerated endothelial recovery, faster integration into the vessel wall and complete re-endothelialization in comparison with thick-struts platforms.28 In addition, our results corroborate the OCT-findings of the Scandinavian Organization for Randomized Trials With Clinical Outcome (SORT OUT) VII trial, which randomly assigned moderately complex lesions to PCI with thick-struts vs. thin-struts BP-DES.29 This imaging-based sub-analysis found a more heterogeneous healing pattern and increased proportion of treated-lesions presenting <90% of strut coverage after implantation of thick-struts as compared to thin-struts BP-DES,30 lending support to a device-specific healing process among biodegradable-polymer drug-eluting stent platforms. Lesions treated with BP-DES presented a greater prevalence of uncovered struts as compared to those treated with new-generation DP-DES. Notably, only one8 out of six trials available for this risk estimate studied thin-struts BP-DES vs. new-generation DP-DES. The clinical impact of OCT-detected incomplete strut coverage remains unknown, though a ratio of uncovered to all struts >30% in 2–3 mm long in-stent sections have been associated with thrombotic coronary occlusions in a histopathological study.31 Despite previous observations found a higher thrombotic risk within 1 year with thick-strut BP-DES as compared to new-generation DP-DES3 and thin-strut BP-DES,29 the paucity of clinical data available in this report precluded assessing whether the impaired coverage observed with thick-strut BP-DES led to worse outcomes as compared with new-generation DP-DES. Lesions treated with BP-DES showed a tendency towards an increased risk for malapposition in comparison with those treated with new-generation DP-DES. The lack of OCT imaging at baseline precludes a distinction between incomplete strut apposition at time of index intervention and acquired malapposition occurring late after implementation of BP-DES. For instance, two studies8,30 have described clusters of malapposed struts and aneurysmatic coronary segments after PCI with thin-struts biodegradable-polymer stent platforms eluting sirolimus, challenging the common perception that aneurysm formation is almost absent with new-generation drug-eluting stent platforms.32 The relative contribution to stent coverage and apposition of different antiproliferative drugs and doses, variable absorption kinetics of coatings and mechanical properties of underlying stent backbones remains unclear and our report highlights once more that performance of DES depends on a complex interplay between all these components. For example, we are unable to decipher whether the increased risk for malapposition observed after PCI with BP-DES vs. new-generation DP-DES was due to vascular toxicity of eluted drug, as observed with early-generation SES,32 or to a transient inflammation owing to sustained degradation process of certain biodegradable polymer formulations investigated in this report.33 Finally, this analysis reaffirms the excellent healing profile of contemporary DP-DES, especially of those with a fluoro-passivated permanent polymer coating, which constituted the majority of the implants in the comparator group analysed in this study. Imaging data in preclinical models support the favourable healing properties of fluoropolymer-based EES as compared to BP-DES either with thick- or thin-strut backbone designs.34 The fluoro-passivation of the durable polymer coating35 in conjunction with the high antiproliferative effect of everolimus36 and a thin-strut platform likely contribute to the same extent for the unprecedented safety and efficacy of these implants as compared with other stent platforms. In this respect, these devices should be further regarded as a benchmark for future comparative studies of vascular healing after coronary stenting. Study limitations The current study has a number of limitations. First, this is a study-level meta-analysis and shares the limitations of such a kind of analyses. In this specific case, despite tougher, a meta-analysis based on individual patient- and lesion-data would have been of help to disclose whether polymers, strut thickness and antiproliferative drugs have a different impact on vascular response. Amongst others, in the absence of lesion-based data comparative analyses of healing profiles belonging to different platforms should be interpreted with caution as differences in implantation techniques could significantly influence imaging results. Second, we focused on a limited number of drug-eluting stent technologies and current results do not apply to other platforms that are not included in this analysis. Finally, OCT imaging data was mostly acquired in well-selected patients and lesions and after a median follow-up of 7 months. In this respect, the findings and the magnitude of the treatment effects observed in the present analysis are neither generalizable to higher-risk subsets of patients nor applicable to a time-point different from that available here. Conclusions In PCI-patients with available OCT imaging at follow-up, BP-DES with thicker backbones delays vascular response as compared with new-generation DP-DES. The higher risk for strut malapposition observed with BP-DES vs. new-generation DP-DES represents an important finding, which requires further investigation. Dedicated randomized trials powered for clinical endpoints are mandatory to address potential clinical sequelae of such imaging data. Supplementary data Supplementary data are available at European Heart Journal – Cardiovascular Imaging online. Conflict of interest: R.C. reports support from the Irish Board for Training in Cardiovascular Medicine sponsored by MSD. D.G. and N.M. are the recipients of a research fellowship grant funded by European Association of Percutaneous Cardiovascular Interventions (EAPCI). R.A.B. reports receiving lecture fees from B. Braun Melsungen AG, Biotronik, and Boston Scientific and research grants to the institution from Boston Scientific and Heartflow, outside the submitted work. A.K. reports holding patents related to drug-eluting stent technology, outside the submitted work. M.J. reports personal fees from Orbus Neich, grants and personal fees from Biotronik, personal fees from Coramaze, personal fees from Astra Zeneca, personal fees from Bristol-Myers-Squibb, outside the submitted work. The other authors declare no potential conflict of interest. References 1 Byrne RA, Kastrati A. No country for old stents? Improving long-term patient outcomes with biodegradable polymer drug-eluting stents. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Jan 2, 2018

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