Immunosuppressive Therapy for Restenosis Prevention after Coronary Bare-Metal Stent Implantation -A Meta-Analysis

Immunosuppressive Therapy for Restenosis Prevention after Coronary Bare-Metal Stent Implantation -A Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Immunosuppressive Therapy for Restenosis Prevention after Coronary Bare-Metal Stent Implantation -A Meta-Analysis Yun-Lang Dai, Jing Zhou, Yu-Feng Jiang, Sheng-Da Hu, Yong-Ming He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.16970/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Previous studies revealed controversial results regarding the prevention of in-stent restenosis after coronary bare-metal stents (BMS) placement with systemic administration of immunosuppressive drugs. We therefore conducted a meta-analysis to investigate the role played by immunosuppressive therapy (IST) in reducing both in-stent restenosis and adverse clinical events after BMS implantation. Methods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases for randomized, controlled studies that investigated the therapeutic effects of IST after BMS insertions. Endpoints assessed were: (1) angiographic restenosis by the end of at least 6 months of follow-up; (2) target vessel revascularization (TVR); and (3) risk of major adverse cardiovascular events (MACE). MACE was defined as death, myocardial infarction and TVR. Results: Nine randomized, controlled trials including 1576 patients (mean age 62 years; follow-up of 6-12 months) were included in this analysis. Meta-analysis showed periprocedural IST + BMS significantly reduced in-stent restenosis as compared to BMS alone (RR: 0.59 [0.39-0.90], P = 0.01). In particular, IST reduced restenosis in high-risk patients (defined as patients with mean reference diameter < 3.0 mm or high periprocedural C-reactive protein level) (RR: 0.34 [0.15,0.74], P = 0.006) rather than in low-risk patients ( P for interaction = 0.06). Similarly, IST also reduced the risk of MACE (RR: 0.63 [0.50-0.80], P < 0.01) and TVR (RR: 0.57 [0.33-0.97], P = 0.04). Conclusions: Periprocedural IST reduces the risk of angiographic restenosis, TVR and MACE in patients with BMS implantation. The advantage of IST is driven mainly by a lower risk of in-stent restenosis in high-risk patients. Key words: immunosuppressive therapy, restenosis, bare-metal stents , meta-analysis Cardiothoracic Surgery immunosuppressive therapy restenosis bare-metal stents meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Background In-stent restenosis after stent insertions remains a challenge of contemporary percutaneous coronary intervention (PCI) [1]. The introduction of drug-eluting stents (DES) has significantly reduced restenosis by comparison with bare-metal stents (BMS) [2]. Nonetheless, DES use has been linked to a high bleeding risk because of prolonged dual antiplatelet therapy, stent thrombosis, and also socioeconomic considerations in developing countries [3]. Furthermore, stenting with the new-generation DES offers a similar risk of adverse events at long-term follow-up as compared to BMS [4].Thus, there is still a considerable proportion of patients receiving BMS implantation in Europe [5] and US [6]. Some human studies have verified the benefits of immunosuppressive therapy (IST) when used systemically in the prevention of restenosis after BMS implantation [7–13]. However, several others indicated no effects on reducing restenosis or clinical outcomes [14–16]. Sardar et al. [17] conducted a meta-analysis in 2012 including 5 studies which investigated the effect of steroids on restenosis in patients undergoing percutaneous coronary angioplasty or BMS implantation, which demonstrated steroids use was associated with a risk reduction in restenosis, mortality and target vessel revascularization (TVR). Cassese et al. [18] performed a meta-analysis by including 7 studies to evaluate the impact of oral IST on target lesion revascularization (TLR) and death/myocardial infarction (MI), which also reported the merits associated with IST in terms of lowering risk of TLR, but failed to demonstrate a reduction in death/ MI. However, the former study included only 3 trials focusing on steroids and did not perform intention-to-treatment analysis; the latter investigated the endpoints not originally focused on by the majority of the studies included. Furthermore, new trials [15, 16] were conducted after the previous meta-analyses. Hence, we aimed to conduct a meta-analysis to confirm the value of IST for the prevention of restenosis detected by angiography surveillance after BMS implantation. methods We conducted our meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines[19]. Search strategy and selection criteria We searched PubMed, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases for relevant studies up to August 2018. The search terms included “glucocorticoid(s)“, “prednisolone” / “prednisone” / “cortisone”, “sirolimus” / “rapamycin”, “immunosuppressive” / “immunosuppression” combined with “restenosis”, “percutaneous coronary intervention”. Reference lists of obtained articles were reviewed. Selection criteria included: (1) randomized controlled trials; (2) comparisons were conducted between IST+BMS group(s) and BMS alone group; (3) intention-to-treat analysis; (4) endpoints could be counted by patient and (5) ≥6-month follow-up after stenting. Two of the authors (Y. L. Dai and J. Zhou) made the same contribution for the searching, screening and selecting the eligible studies. Conflicts were discussed with a third investigator (Y. M. He). Data extraction and quality assessment We extracted study data as follows: first author; year of publication; design details; number of participants; protocol of IST; events of restenosis; TVR; and major adverse cardiovascular events (MACE), as well as useful data such as patient demographics and the duration of follow-up. We performed the assessment of bias using the Cochrane Collaboration tools based on methodological items, including randomization, allocation concealment, blinding, incomplete reporting of outcomes, selective presentation of outcomes, and other biases[20]. Outcomes assessment The primary endpoint was in-stent restenosis detected by routine angiographic surveillance after stenting during follow-up of at least 6 months. Secondary endpoints were TVR (defined as any repeat revascularization of the target vessel) and MACE (defined as death, MI and TVR). Definitions of other endpoints are shown in supplemental table 2. Statistical analysis Intension-to-treat analysis was used for outcome analysis. For the meta-analysis, relative risks (RRs) and 95% confidence intervals (CIs) for each study were calculated. Pooled RRs and CIs were estimated either by a fixed-effect model (Mantel-Haenszel method) or, in the presence of heterogeneity (defined as I 2 value >50%), by random-effect model (DerSimonian-Laird method). We investigated publication bias via drawing Begg’s funnel plot and performing Harbord test. To help explain heterogeneity, subgroup analyses and Monte-Carlo permutation tests for meta-regression were performed by grouping studies according to sample sizes, features of patients (patients with mean reference diameter <3.0 mm or elevated C-reactive protein after PCI were considered as high-risk patients, otherwise defined as low-risk patients), therapies and publication year. Sensitivity analyses were conducted using the “1-study removed” method to determine the impact of any single study on main findings. Interaction between subgroup and treatment was assessed by permutation test at the P < 0.10 level of significance. All analyses were carried out using STATA version 14.0 (Stata Corp, College Station, TX). P value less than 0.05 was considered statistically significant, except where otherwise specified. Results Literature search and selection The final search on September 10, 2018, resulted in 1137 articles. The majority of the articles were precluded because of duplicates, reviews, commentary articles, unrelated topic and animal studies. Twenty-eight full-text articles were read, of which 19 were excluded, including 5 studies without randomized designs, 6 reviews and 8 irrelevant studies. Hence, 9 studies [7, 8, 10–16] were included in this meta-analysis, including 1576 patients, of whom 848 (54%) received IST. The review process is shown in Fig. 1. Study characteristics and study quality The supplemental table 1 presents an overview of the included studies. Patients with indications for revascularization were randomized to IST + BMS versus BMS alone. The IST consisted of steroids or sirolimus in all cases and was administrated by oral route except in two studies. In five trials, sirolimus dose varied between 2 and 3 mg per day for a duration of 7–30 days after index PCI [8, 10–12]. Oral steroids were given to patients with a duration of 28–45 days in three studies [7, 13, 16]. In studies using non-oral steroids, IST was administrated once or twice in total [14, 15]. Per protocol endpoints including angiographic and clinical endpoints and their definitions were listed in supplemental table 1 and table 2. Few key differences were found among these studies with respect to definition of restenosis, TVR, TLR, death, and MACE. Quality assessments of included studies were shown in supplemental table 3. Study and patient characteristics were available for all studies (Table 1). The sample sizes ranged between 80 and 315, whereas three studies only included equal to or less than 100 cases. The average age of patients enrolled ranged from 58 (10) to 65 (9) years, and male patients dominated all of studies. Over half of the patients were diagnosed with acute coronary syndrome (ACS) at admission in 6 trials, and reference diameter (RD) before PCI ranged between 2.59 mm and 3.41 mm. Angiographic surveillance were made in majority of patients in 8 studies. Mean clinical follow-up duration varied from 6 to 12 months. Primary endpoint The primary endpoint (in-stent restenosis) was presented in 7 of 9 studies after precluding 2 trials [11, 13], among which one didn’t perform routine angiographic surveillance and another reported events not counted by patient. In total, 273 of 1218 (22.4%) patients met the restenosis criteria detected by angiographic surveillance after 6–9 months. A random-effect model was used to estimate the combined RRs and 95% CIs according to I 2, whichshowed that periprocedural IST+BMS significantly reduced the risk of restenosis as compared to BMS alone (18.7% versus 27.0%, RR: 0.59 [0.39–0.90], P = 0.01; I 2 = 64.2%, P for heterogeneity = 0.01) (Fig. 2A). Secondary endpoints Event rates were low for death (1%), MI (1%) and TLR (4 studies reported the incidence), thus combining estimated RRs was performed for TVR and MACE. Eight studies reported the incidence of MACE, including 748 patients in IST+BMS group and 628 in BMS alone group. A significant reduction in MACE was observed among those assigned to IST+BMS group (14.3% versus 21.2%, RR: 0.63 [0.50–0.80], P < 0.01; I 2 = 32.0%, P for heterogeneity = 0.17) (Fig. 2B). The risk of TVR, reported in 6 studies, were also reduced with IST (12.4% versus 18.6%, RR: 0.57 [0.33–0.97], P = 0.04; I 2 = 61.2%, P for heterogeneity = 0.02) (Fig. 2C). Subgroup analysis on the primary endpoint Subgroup analyses were conducted to explore potential sources of heterogeneity across studies by dividing these studies into several groups according to sample sizes, features of patients, different therapies and publication year. Subgroup analyses based on sample sizes and features of patients consistently revealed significant between-group heterogeneity ( P for interaction = 0.02 and 0.06, respectively). In the subgroup with small sample sizes, IST lowered the risk of restenosis (RR: 0.23 [0.13,0.42], P < 0.001; I 2 = 0%, P for heterogeneity = 0.69) as compared to BMS alone. Similarly, the combined results of 3 trials with high-risk patients showed IST reduced restenosis (RR: 0.34 [0.15,0.74], P = 0.006; I 2 = 71%, P for heterogeneity = 0.02) (Fig. 3A). However, the benefit was observed neither in the subgroup with large sample sizes, nor in the subgroup with low-risk patients. Next, in the subgroup analysis based on different drug use, difference occurred between sirolimus subgroup (RR: 0.37 [0.15,0.91], P = 0.03) and steroid subgroup (RR: 0.79 [0.50,1.25], P = 0.31). Nonetheless, between-group heterogeneity test did not reach statistical significance ( P for interaction = 0.20) (Fig. 3A). Final subgroup analysis was performed according to publication year. The combined results of trials published before 2010 revealed pronounced IST effect on restenosis (RR: 0.53 [0.31,0.92], P = 0.03). However, interaction test did not show between-group heterogeneity ( P for interaction = 0.64) (Fig. 3A). Subgroup analysis on the secondary endpoints In the subgroup analyses, sample size was the only factor influencing the effect of IST on the risk of MACE according to Monte Carlo permutation result ( P for interaction = 0.02). In the subgroup with smaller sample sizes, IST+BMS versus BMS reduced the risk of MACE (RR: 0.32 [0.19,0.54], P < 0.001; I 2 = 0%, P for heterogeneity = 0.58), while another subgroup with larger sample sizes showed a similar risk of MACE. (Fig. 3B). Similarly, sample size was also the main source of heterogeneity across studies regarding the effects of IST on the risk of TVR ( P for interaction = 0.03). Whereas subgroup analysis according to features of patients, different therapies and publication year revealed generally consistent results (Fig. 3C). Sensitivity analysis and publication bias Sensitivity analysis for the primary endpoint was performed to investigate whether the lack of each study will alter the pooled RRs (Fig. 4B). No results changed materially after an individual study was omitted. A Begg’s funnel plot for the primary endpoint rate showed the studies were equally distributed on the two sides (Fig. 4A). Moreover, Harbord test was performed to further identify the underlying heterogeneity and its results indicated the absence of bias ( P = 0.15). discussion In the present meta-analysis of 9 unique studies including 1576 patients with a follow-up of 6–12 months, we demonstrate that IST + BMS reduced the risk of restenosis, MACE, and TVR as compared to BMS alone. Patients with high-risk features responded favorably to the IST. As a main finding, IST + BMS versus BMS alone decreases restenosis. However, this finding should be interpreted with caution as an obvious heterogeneity was observed in this analysis. Thus, subgroup analyses were carried out. Subgroup analysis according to the features of patients showed IST could only reduce restenosis in high-risk patients, which was further confirmed by interaction test with meta-regression ( P for interaction = 0.06). Surprisingly, all patients included in 3 trials with small sample sizes had high-risk features in the subgroup analysis by sample sizes, which may explain why IST reduced the risk of restenosis only after combining studies with small sample sizes. Finally, subgroup analyses based on different therapies and publication year both showed some degree of heterogeneity, although P value for interaction didn’t reach statistical significance. As illustrated by experimental studies, the inflammatory reaction plays an essential role in the process of neointimal proliferation [21]. Inhibition of cell proliferation and migration by releasing immunosuppressive drugs in situ is the intrinsic feature of DES [22]. Whether systemic administration of these drugs, focusing on steroids and sirolimus in previous studies, could reduce restenosis as DES did has attracted attention for a long period [23]. Our meta-analysis revealed the favorable effect of IST on restenosis. Notably, the analysis showed high-risk patients would benefit more from IST, suggesting patients with high-risk features (mean reference diameter <3.0mm [24], elevated C-reactive protein after PCI [25]) may have more remarkable inflammation reactions in situ and be more likely to experiencing restenosis after BMS implantation as compared to those without these features. Furthermore, higher dose intensity for a longer period might be needed to reduce restenosis as illustrated by comparing SSTARS study [16] and IMPRESS-LD study [26] with IMPRESS(2) [7, 9] studies. Although permute tests didn’t show significant heterogeneity between steroid subgroup and sirolimus subgroup, different effects may exist. BMS+IST versus BMS alone reduced the risk of MACE and TVR at mid-term follow-up. These results merit cautious discussion since the duration of follow-up differs and we can not calculate hazard ratios (HRs) due to lack of individual patient data. Unlike immunosuppressive drugs acting within a limited vessel in DES, systemic use of IST may bring about unsought adverse reactions. However, in the included studies only a small number of patients experienced major side effects and discontinued IST. Moreover, the studies with longer follow-up didn’t reveal higher incidence of diabetes, malignancies, and other major adverse effects in IST groups in comparison with control arms[27, 28]. Our study has several limitations. First, the sample sizes in some studies were relatively small, with a sample size less than or equal to 100. Second, several estimated effects (e.g. 1 trial did not report the results of clinical endpoints) could not be obtained in some trials. Third, we are unable to calculate HRs, which have better validities in the occurrence of different follow-up durations, and can not control for traditional risk factors due to having no access to all raw datasets. conclusion The present meta-analysis demonstrates that IST reduces the risk of restenosis, TVR and MACE as compared with BMS alone. The benefits of the IST are mainly driven by a lower risk of restenosis in high-risk patients. abbreviations ACS: acute coronary syndrome; BMS: bare-metal stent(s); CIs: confidence intervals; DES: drug-eluting stent(s); HRs: hazard ratios; IST: immunosuppressive therapy; MACE: major adverse cardiovascular event(s); MI: myocardial infarction; PCI: percutaneous coronary intervention; RD: reference diameter; RRs: relative risks; TLR: target vessel revascularization; TVR: target vessel revascularization declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and material All data are presented within the manuscript. Raw date can be available by corresponding author per request. Competing interests The author declare that they have no competing interests. Funding No funding was received for this study. Authors’ contributions Y-M He and Y-L Dai designed this study. Y-L Dai and JZ made substantial contributions to literature searching, eligible studies selecting and data extracting. Y-L Dai, JZ, Y-F Jiang and S-D Hu were involved in data analysis. Y-M He, Y-L Dai and JZ wrote the manuscript. All author approved the final version of the manuscript. Acknowledgements None. references 1.Alfonso F, Byrne RA, Rivero F, Kastrati A: Current treatment of in-stent restenosis. 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JACC Cardiovasc Interv 2009, 2( 11):1142–1148. 28.Ribichini F, Tomai F, Pesarini G, Zivelonghi C, Rognoni A, De Luca G, Boccuzzi G, Presbitero P, Ferrero V, Ghini AS et al: Long-term clinical follow-up of the multicentre, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: Cortisone plus BMS or DES veRsus BMS alone to EliminAte Restenosis (CEREA-DES). Eur Heart J 2013, 34( 23):1740–1748. tables Table 1. Characteristics of patients included in the meta-analysis stratified by trial. Trial N Age , years Males (%) ACS (%) LAD (%) # RD pre, mm IST method Surveillance angiography (%) Mean follow up time, months Lee et al. 14 140 58(9) 66 61 46 3.41(0.38) before PCI: 1g methylprednisolone i.v. 91 10.3 IMPRESS 7 83 64(9) 83 11 52 3.10(0.05) 72h to 45 days after PCI: prednisone oral 98 12 OSIRIS 8 300 65(9) 78 0 49 2.59(0.52) 48h prior to 7 days after PCI: sirolimus oral 86 12 ORAR II 10 100 65(9) 91 65 47 2.94(0.56) 2.7h prior to 14 days after PCI: sirolimus oral 87 12 Stojkovic et al. 12 80 58(10) 70 54 41 2.59(0.44) post-procedure to 30 days: sirolimus oral 90 6.8 Cernigliaro et al. 11 108 63(11) 84 68 76 2.93(0.72) post-procedure to 30 days: sirolimus oral 96 12 Namdari et al. 15 200 60(7) 56 N/A N/A N/A two doses at 2-week interval: prednisolone i.m. 100 N/A CEREA -DES 13 250 64(9) 84 61 62 3.15(0.53) post-procedure to 40 days: prednisone oral N/A 12 SSTARS 16 315 60 85 58 N/A 3.18(0.42) 6h prior to 28 days after PCI: prednisolone oral 91 6 Data are mean (SD), unless otherwise indicated. # variables counted by patient. ACS: acute coronary syndrome; IST: immunosuppressive therapy; i.v.: intravenous; i.m.: intramuscular; LAD: left anterior descending artery; PCI: percutaneous coronary intervention; RD pre: reference diameter before intervention; N/A: not applicable. Trial acronyms: IMPRESS: Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Stent Implantation; OSIRIS: Oral Sirolimus to Inhibit Recurrent In-stent Stenosis; ORAR: Oral Rapamycin in Argentina; CEREA-DES: Cortisone plus BMS or DES versus BMS alone to eliminate restenosis; SSTARS: STeroids and Stents Against Re-Stenosis. Supplementary Files prismacheklist1.0.doc supplementarydata.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7607","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":207636,"identity":"cf613378-0309-46d8-a0f0-238a20c47061","order_by":1,"name":"Yun-Lang Dai","email":"","orcid":"https://orcid.org/0000-0002-6565-8781","institution":"First Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yun-Lang","middleName":"","lastName":"Dai","suffix":""},{"id":207637,"identity":"59b55f29-42f2-4269-bf57-cb0a35c118d2","order_by":2,"name":"Jing Zhou","email":"","orcid":"","institution":"First Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Zhou","suffix":""},{"id":207638,"identity":"68ebe280-acc9-4e4e-8aab-2038244739af","order_by":3,"name":"Yu-Feng Jiang","email":"","orcid":"","institution":"First Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yu-Feng","middleName":"","lastName":"Jiang","suffix":""},{"id":207639,"identity":"c75510cb-7c28-4283-a857-580dc91f2654","order_by":4,"name":"Sheng-Da Hu","email":"","orcid":"","institution":"First Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sheng-Da","middleName":"","lastName":"Hu","suffix":""},{"id":207640,"identity":"8aba7608-669f-4ce3-9c50-9cbaeaa8d4e3","order_by":5,"name":"Yong-Ming He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYBACAyjNw8DAfICBgQ3ETiBaC1sCaVpAugyI02LO3mP4uODXNhlz/jWfP/OU2THws+cYMPzcgVuLZc8ZY+OZfbd5LGe83SbNcy6ZQbLnjQFj7xk8DruRYybN23Obx+DG2W3MvG3MIBEDZsY2PFruv4FpOfP4M29bPYM9QS03eMykeX4AtZzvYZDmbTvMYCBBSMuZtGJj3gaQLWxmknPOHeeROPOs4GAvPi3HD298zPPntr3B+cOPP7wpq5bjb0/e+OAnHi0MDBwGDGBnSCSAuTwg4gA+DQwM7A8YGP4AaX4C6kbBKBgFo2DkAgC8iFI5us0eFwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3154-2892","institution":"","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yong-Ming","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2019-11-04 15:01:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.2.16970/v1","doiUrl":"https://doi.org/10.21203/rs.2.16970/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":154811,"identity":"2dff60f1-ae3e-43a2-911d-4f5390a1a5d1","added_by":"auto","created_at":"2019-11-09 01:10:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":122404,"visible":true,"origin":"","legend":"The complete procedure of the study selection and exclusion. Nine studies were finally included.","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/17932870-d259-4411-a7bd-830f8863928c/v1/Fig. 1.jpg"},{"id":154814,"identity":"1158b50b-f080-4157-aaab-b26aa9f508bb","added_by":"auto","created_at":"2019-11-09 01:10:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":231007,"visible":true,"origin":"","legend":"Risk estimates of primary and secondary outcomes for IST + BMS versus BMS alone. Forest plots show results for rates of restenosis (A), rates of target vessel revascularization (B), and risk of major adverse cardiovascular events (C). IST: immunosuppressive therapy. CI: confidence interval. Trial acronyms are as in the table 1.","description":"","filename":"Fig.2IST.jpg","url":"https://assets-eu.researchsquare.com/files/17932870-d259-4411-a7bd-830f8863928c/v1/Fig. 2-IST.jpg"},{"id":154815,"identity":"c392dd84-1a02-44d5-add6-4490b3404a81","added_by":"auto","created_at":"2019-11-09 01:10:53","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":219519,"visible":true,"origin":"","legend":"Subgroup analyses for the effects of IST + BMS versus BMS alone on rates of restenosis (A), rates of target vessel revascularization (B), and risk of major adverse cardiovascular events (C). Abbreviations are as in Fig.2.","description":"","filename":"Fig.3IST.jpg","url":"https://assets-eu.researchsquare.com/files/17932870-d259-4411-a7bd-830f8863928c/v1/Fig. 3-IST.jpg"},{"id":154816,"identity":"f92bce4a-9a85-4f69-b6bd-ea620243e8c1","added_by":"auto","created_at":"2019-11-09 01:10:53","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":51426,"visible":true,"origin":"","legend":"Begg’s funnel plot with pseudo 95% confidence limits is drawn (A). Meta-analysis random-effects estimates are computed omitting one study at time (B). Rates of restenosis was extracted for analysis. lnrr: logarithm of risk ratio. Other abbreviations are as in Fig.2.","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/17932870-d259-4411-a7bd-830f8863928c/v1/Fig. 4.jpg"},{"id":13478516,"identity":"31f0cb5d-7652-479b-9c7d-2e5099525d9a","added_by":"auto","created_at":"2021-09-16 21:35:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":836982,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7607/v1/2ced8007-e7ac-4ee9-89b5-4d3bd6ae4893.pdf"},{"id":154813,"identity":"f98c28ef-6e4f-4c69-acb6-a7e86948ab57","added_by":"auto","created_at":"2019-11-09 01:10:52","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":74240,"visible":true,"origin":"","legend":"","description":"","filename":"prismacheklist1.0.doc","url":"https://assets-eu.researchsquare.com/files/17932870-d259-4411-a7bd-830f8863928c/v1/prisma-cheklist1.0.doc"},{"id":154810,"identity":"4ca5dd04-dda6-4603-85a6-4dff21475fc1","added_by":"auto","created_at":"2019-11-09 01:10:52","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":79388,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarydata.docx","url":"https://assets-eu.researchsquare.com/files/17932870-d259-4411-a7bd-830f8863928c/v1/supplementary data.docx"}],"financialInterests":"","formattedTitle":"Immunosuppressive Therapy for Restenosis Prevention after Coronary Bare-Metal Stent Implantation -A Meta-Analysis","fulltext":[{"header":"Background","content":"\n\u003cp\u003eIn-stent restenosis after stent insertions remains a challenge of contemporary percutaneous coronary intervention (PCI) [1]. The introduction of drug-eluting stents (DES) has significantly reduced restenosis by comparison with bare-metal stents (BMS) [2]. Nonetheless, DES use has been linked to a high bleeding risk because of prolonged dual antiplatelet therapy, stent thrombosis, and also socioeconomic considerations in developing countries [3]. Furthermore, stenting with the new-generation DES offers a similar risk of adverse events at long-term follow-up as compared to BMS [4].Thus, there is still a considerable proportion of patients receiving BMS implantation in Europe [5] and US [6].\u003c/p\u003e\n\u003cp\u003eSome human studies have verified the benefits of immunosuppressive therapy (IST) when used systemically in the prevention of restenosis after BMS implantation [7–13]. However, several others indicated no effects on reducing restenosis or clinical outcomes [14–16]. Sardar et al. [17] conducted a meta-analysis in 2012 including 5 studies which investigated the effect of steroids on restenosis in patients undergoing percutaneous coronary angioplasty or BMS implantation, which demonstrated steroids use was associated with a risk reduction in restenosis, mortality and target vessel revascularization (TVR). Cassese et al. [18] performed a meta-analysis by including 7 studies to evaluate the impact of oral IST on target lesion revascularization (TLR) and death/myocardial infarction (MI), which also reported the merits associated with IST in terms of lowering risk of TLR, but failed to demonstrate a reduction in death/ MI. However, the former study included only 3 trials focusing on steroids and did not perform intention-to-treatment analysis; the latter investigated the endpoints not originally focused on by the majority of the studies included. Furthermore, new trials [15, 16] were conducted after the previous meta-analyses. Hence, we aimed to conduct a meta-analysis to confirm the value of IST for the prevention of restenosis detected by angiography surveillance after BMS implantation.\u003c/p\u003e\n"},{"header":"methods","content":"\n\u003cp\u003eWe conducted our meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines[19].\u003c/p\u003e\n\u003ch3\u003eSearch strategy and selection criteria\u003c/h3\u003e\n\u003cp\u003eWe searched PubMed, Web of Science, Cochrane Central Register of Controlled Trials, and \u003ca href=\"http://ClinicalTrials.gov\"\u003eClinicalTrials.gov\u003c/a\u003e databases for relevant studies up to August 2018. The search terms included “glucocorticoid(s)“, “prednisolone” / “prednisone” / “cortisone”, “sirolimus” / “rapamycin”, “immunosuppressive” / “immunosuppression” combined with “restenosis”, “percutaneous coronary intervention”. Reference lists of obtained articles were reviewed. Selection criteria included: (1) randomized controlled trials; (2) comparisons were conducted between IST+BMS group(s) and BMS alone group; (3) intention-to-treat analysis; (4) endpoints could be counted by patient and (5) ≥6-month follow-up after stenting.\u003c/p\u003e\n\u003cp\u003eTwo of the authors (Y. L. Dai and J. Zhou) made the same contribution for the searching, screening and selecting the eligible studies. Conflicts were discussed with a third investigator (Y. M. He).\u003c/p\u003e\n\u003ch3\u003eData extraction and quality assessment\u003c/h3\u003e\n\u003cp\u003eWe extracted study data as follows: first author; year of publication; design details; number of participants; protocol of IST; events of restenosis; TVR; and major adverse cardiovascular events (MACE), as well as useful data such as patient demographics and the duration of follow-up.\u003c/p\u003e\n\u003cp\u003eWe performed the assessment of bias using the Cochrane Collaboration tools based on methodological items, including randomization, allocation concealment, blinding, incomplete reporting of outcomes, selective presentation of outcomes, and other biases[20].\u003c/p\u003e\n\u003ch3\u003eOutcomes assessment\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was in-stent restenosis detected by routine angiographic surveillance after stenting during follow-up of at least 6 months. Secondary endpoints were TVR (defined as any repeat revascularization of the target vessel) and MACE (defined as death, MI and TVR). Definitions of other endpoints are shown in supplemental table 2.\u003c/p\u003e\n\u003ch3\u003eStatistical analysis\u003c/h3\u003e\n\u003cp\u003eIntension-to-treat analysis was used for outcome analysis. For the meta-analysis, relative risks (RRs) and 95% confidence intervals (CIs) for each study were calculated. Pooled RRs and CIs were estimated either by a fixed-effect model (Mantel-Haenszel method) or, in the presence of heterogeneity (defined as\u003cem\u003e I\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003evalue \u0026gt;50%), by random-effect model (DerSimonian-Laird method). We investigated publication bias via drawing Begg’s funnel plot and performing Harbord test. To help explain heterogeneity, subgroup analyses and Monte-Carlo permutation tests for meta-regression were performed by grouping studies according to sample sizes, features of patients (patients with mean reference diameter \u0026lt;3.0 mm or elevated C-reactive protein after PCI were considered as high-risk patients, otherwise defined as low-risk patients), therapies and publication year. Sensitivity analyses were conducted using the “1-study removed” method to determine the impact of any single study on main findings. Interaction between subgroup and treatment was assessed by permutation test at the \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.10 level of significance. All analyses were carried out using STATA version 14.0 (Stata Corp, College Station, TX). \u003cem\u003eP\u003c/em\u003e value less than 0.05 was considered statistically significant, except where otherwise specified.\u003c/p\u003e"},{"header":"Results","content":"\n\u003ch3\u003eLiterature search and selection\u003c/h3\u003e\n\u003cp\u003eThe final search on September 10, 2018, resulted in 1137 articles. The majority of the articles were precluded because of duplicates, reviews, commentary articles, unrelated topic and animal studies. Twenty-eight full-text articles were read, of which 19 were excluded, including 5 studies without randomized designs, 6 reviews and 8 irrelevant studies. Hence, 9 studies [7, 8, 10–16] were included in this meta-analysis, including 1576 patients, of whom 848 (54%) received IST. The review process is shown in Fig. 1.\u003c/p\u003e\n\u003ch3\u003eStudy characteristics and study quality\u003c/h3\u003e\n\u003cp\u003eThe supplemental table 1 presents an overview of the included studies. Patients with indications for revascularization were randomized to IST + BMS versus BMS alone. The IST consisted of steroids or sirolimus in all cases and was administrated by oral route except in two studies. In five trials, sirolimus dose varied between 2 and 3 mg per day for a duration of 7–30 days after index PCI [8, 10–12]. Oral steroids were given to patients with a duration of 28–45 days in three studies [7, 13, 16]. In studies using non-oral steroids, IST was administrated once or twice in total [14, 15]. Per protocol endpoints including angiographic and clinical endpoints and their definitions were listed in supplemental table 1 and table 2. Few key differences were found among these studies with respect to definition of restenosis, TVR, TLR, death, and MACE. Quality assessments of included studies were shown in supplemental table 3.\u003c/p\u003e\n\u003cp\u003eStudy and patient characteristics were available for all studies (Table 1). The sample sizes ranged between 80 and 315, whereas three studies only included equal to or less than 100 cases. The average age of patients enrolled ranged from 58 (10) to 65 (9) years, and male patients dominated all of studies. Over half of the patients were diagnosed with acute coronary syndrome (ACS) at admission in 6 trials, and reference diameter (RD) before PCI ranged between 2.59 mm and 3.41 mm. Angiographic surveillance were made in majority of patients in 8 studies. Mean clinical follow-up duration varied from 6 to 12 months.\u003c/p\u003e\n\u003ch3\u003ePrimary endpoint\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint (in-stent restenosis) was presented in 7 of 9 studies after precluding 2 trials [11, 13], among which one didn’t perform routine angiographic surveillance and another reported events not counted by patient. In total, 273 of 1218 (22.4%) patients met the restenosis criteria detected by angiographic surveillance after 6–9 months. A random-effect model was used to estimate the combined RRs and 95% CIs according to \u003cem\u003eI\u003csup\u003e2,\u003c/sup\u003e\u003c/em\u003e whichshowed that periprocedural IST+BMS significantly reduced the risk of restenosis as compared to BMS alone (18.7% versus 27.0%, RR: 0.59 [0.39–0.90], \u003cem\u003eP \u003c/em\u003e = 0.01; \u003cem\u003eI\u003csup\u003e2 \u003c/sup\u003e\u003c/em\u003e = 64.2%, \u003cem\u003eP\u003c/em\u003e for heterogeneity = 0.01) (Fig. 2A).\u003c/p\u003e\n\u003ch3\u003eSecondary endpoints\u003c/h3\u003e\n\u003cp\u003eEvent rates were low for death (1%), MI (1%) and TLR (4 studies reported the incidence), thus combining estimated RRs was performed for TVR and MACE. Eight studies reported the incidence of MACE, including 748 patients in IST+BMS group and 628 in BMS alone group. A significant reduction in MACE was observed among those assigned to IST+BMS group (14.3% versus 21.2%, RR: 0.63 [0.50–0.80], \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01; \u003cem\u003eI\u003csup\u003e2 \u003c/sup\u003e\u003c/em\u003e = 32.0%, \u003cem\u003eP\u003c/em\u003e for heterogeneity = 0.17) (Fig. 2B). The risk of TVR, reported in 6 studies, were also reduced with IST (12.4% versus 18.6%, RR: 0.57 [0.33–0.97], \u003cem\u003eP \u003c/em\u003e = 0.04; \u003cem\u003eI\u003csup\u003e2 \u003c/sup\u003e\u003c/em\u003e = 61.2%, \u003cem\u003eP\u003c/em\u003e for heterogeneity = 0.02) (Fig. 2C).\u003c/p\u003e\n\u003ch3\u003eSubgroup analysis on the primary endpoint\u003c/h3\u003e\n\u003cp\u003eSubgroup analyses were conducted to explore potential sources of heterogeneity across studies by dividing these studies into several groups according to sample sizes, features of patients, different therapies and publication year.\u003c/p\u003e\n\u003cp\u003eSubgroup analyses based on sample sizes and features of patients consistently revealed significant between-group heterogeneity (\u003cem\u003eP \u003c/em\u003efor interaction = 0.02 and 0.06, respectively). In the subgroup with small sample sizes, IST lowered the risk of restenosis (RR: 0.23 [0.13,0.42], \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001; \u003cem\u003eI\u003csup\u003e2 \u003c/sup\u003e\u003c/em\u003e = 0%, \u003cem\u003eP\u003c/em\u003e for heterogeneity = 0.69) as compared to BMS alone. Similarly, the combined results of 3 trials with high-risk patients showed IST reduced restenosis (RR: 0.34 [0.15,0.74], \u003cem\u003eP \u003c/em\u003e = 0.006; \u003cem\u003eI \u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e = 71%, \u003cem\u003eP\u003c/em\u003e for heterogeneity = 0.02) (Fig. 3A). However, the benefit was observed neither in the subgroup with large sample sizes, nor in the subgroup with low-risk patients.\u003c/p\u003e\n\u003cp\u003eNext, in the subgroup analysis based on different drug use, difference occurred between sirolimus subgroup (RR: 0.37 [0.15,0.91], \u003cem\u003eP = \u003c/em\u003e0.03) and steroid subgroup (RR: 0.79 [0.50,1.25],\u003cem\u003e P\u003c/em\u003e = 0.31). Nonetheless, between-group heterogeneity test did not reach statistical significance (\u003cem\u003eP \u003c/em\u003efor interaction = 0.20) (Fig. 3A). Final subgroup analysis was performed according to publication year. The combined results of trials published before 2010 revealed pronounced IST effect on restenosis (RR: 0.53 [0.31,0.92], \u003cem\u003eP \u003c/em\u003e = 0.03). However, interaction test did not show between-group heterogeneity (\u003cem\u003eP \u003c/em\u003efor interaction = 0.64) (Fig. 3A).\u003c/p\u003e\n\u003ch3\u003eSubgroup analysis on the secondary endpoints\u003c/h3\u003e\n\u003cp\u003eIn the subgroup analyses, sample size was the only factor influencing the effect of IST on the risk of MACE according to Monte Carlo permutation result (\u003cem\u003eP\u003c/em\u003e for interaction = 0.02). In the subgroup with smaller sample sizes, IST+BMS versus BMS reduced the risk of MACE (RR: 0.32 [0.19,0.54], \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001; \u003cem\u003eI\u003csup\u003e2 \u003c/sup\u003e\u003c/em\u003e = 0%, \u003cem\u003eP\u003c/em\u003e for heterogeneity = 0.58), while another subgroup with larger sample sizes showed a similar risk of MACE. (Fig. 3B).\u003c/p\u003e\n\u003cp\u003eSimilarly, sample size was also the main source of heterogeneity across studies regarding the effects of IST on the risk of TVR (\u003cem\u003eP \u003c/em\u003efor interaction = 0.03). Whereas subgroup analysis according to features of patients, different therapies and publication year revealed generally consistent results (Fig. 3C).\u003c/p\u003e\n\u003ch3\u003eSensitivity analysis and publication bias\u003c/h3\u003e\n\u003cp\u003eSensitivity analysis for the primary endpoint was performed to investigate whether the lack of each study will alter the pooled RRs (Fig. 4B). No results changed materially after an individual study was omitted. A Begg’s funnel plot for the primary endpoint rate showed the studies were equally distributed on the two sides (Fig. 4A). Moreover, Harbord test was performed to further identify the underlying heterogeneity and its results indicated the absence of bias (\u003cem\u003eP \u003c/em\u003e = 0.15).\u003c/p\u003e"},{"header":"discussion","content":"\n\u003cp\u003eIn the present meta-analysis of 9 unique studies including 1576 patients with a follow-up of 6–12 months, we demonstrate that IST + BMS reduced the risk of restenosis, MACE, and TVR as compared to BMS alone. Patients with high-risk features responded favorably to the IST.\u003c/p\u003e\n\u003cp\u003eAs a main finding, IST + BMS versus BMS alone decreases restenosis. However, this finding should be interpreted with caution as an obvious heterogeneity was observed in this analysis. Thus, subgroup analyses were carried out. Subgroup analysis according to the features of patients showed IST could only reduce restenosis in high-risk patients, which was further confirmed by interaction test with meta-regression (\u003cem\u003eP \u003c/em\u003efor interaction = 0.06). Surprisingly, all patients included in 3 trials with small sample sizes had high-risk features in the subgroup analysis by sample sizes, which may explain why IST reduced the risk of restenosis only after combining studies with small sample sizes. Finally, subgroup analyses based on different therapies and publication year both showed some degree of heterogeneity, although \u003cem\u003eP\u003c/em\u003e value for interaction didn’t reach statistical significance.\u003c/p\u003e\n\u003cp\u003eAs illustrated by experimental studies, the inflammatory reaction plays an essential role in the process of neointimal proliferation [21]. Inhibition of cell proliferation and migration by releasing immunosuppressive drugs in situ is the intrinsic feature of DES [22]. Whether systemic administration of these drugs, focusing on steroids and sirolimus in previous studies, could reduce restenosis as DES did has attracted attention for a long period [23].\u003c/p\u003e\n\u003cp\u003eOur meta-analysis revealed the favorable effect of IST on restenosis. Notably, the analysis showed high-risk patients would benefit more from IST, suggesting patients with high-risk features (mean reference diameter \u0026lt;3.0mm [24], elevated C-reactive protein after PCI [25]) may have more remarkable inflammation reactions in situ and be more likely to experiencing restenosis after BMS implantation as compared to those without these features. Furthermore, higher dose intensity for a longer period might be needed to reduce restenosis as illustrated by comparing SSTARS study [16] and IMPRESS-LD study [26] with IMPRESS(2) [7, 9] studies. Although permute tests didn’t show significant heterogeneity between steroid subgroup and sirolimus subgroup, different effects may exist.\u003c/p\u003e\n\u003cp\u003eBMS+IST versus BMS alone reduced the risk of MACE and TVR at mid-term follow-up. These results merit cautious discussion since the duration of follow-up differs and we can not calculate hazard ratios (HRs) due to lack of individual patient data.\u003c/p\u003e\n\u003cp\u003eUnlike immunosuppressive drugs acting within a limited vessel in DES, systemic use of IST may bring about unsought adverse reactions. However, in the included studies only a small number of patients experienced major side effects and discontinued IST. Moreover, the studies with longer follow-up didn’t reveal higher incidence of diabetes, malignancies, and other major adverse effects in IST groups in comparison with control arms[27, 28].\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. First, the sample sizes in some studies were relatively small, with a sample size less than or equal to 100. Second, several estimated effects (e.g. 1 trial did not report the results of clinical endpoints) could not be obtained in some trials. Third, we are unable to calculate HRs, which have better validities in the occurrence of different follow-up durations, and can not control for traditional risk factors due to having no access to all raw datasets.\u003c/p\u003e"},{"header":"conclusion ","content":"\u003cp\u003eThe present meta-analysis demonstrates that IST reduces the risk of restenosis, TVR and MACE as compared with BMS alone. The benefits of the IST are mainly driven by a lower risk of restenosis in high-risk patients.\u003c/p\u003e"},{"header":"abbreviations ","content":"\n\u003cp\u003eACS: acute coronary syndrome; BMS: bare-metal stent(s); CIs: confidence intervals; DES: drug-eluting stent(s); HRs: hazard ratios; IST: immunosuppressive therapy; MACE: major adverse cardiovascular event(s); MI: myocardial infarction; PCI: percutaneous coronary intervention; RD: reference diameter; RRs: relative risks; TLR: target vessel revascularization; TVR: target vessel revascularization\u003c/p\u003e"},{"header":"declarations ","content":"\n\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eAvailability of data and material\u003c/h3\u003e\n\u003cp\u003eAll data are presented within the manuscript. Raw date can be available by corresponding author per request.\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u003c/h3\u003e\n\u003cp\u003eThe author declare that they have no competing interests.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003ch3\u003eAuthors’ contributions\u003c/h3\u003e\n\u003cp\u003eY-M He and Y-L Dai designed this study. Y-L Dai and JZ made substantial contributions to literature searching, eligible studies selecting and data extracting. Y-L Dai, JZ, Y-F Jiang and S-D Hu were involved in data analysis. Y-M He, Y-L Dai and JZ wrote the manuscript. All author approved the final version of the manuscript.\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"references","content":"\n\u003cp\u003e1.Alfonso F, Byrne RA, Rivero F, Kastrati A: \u003cem\u003eCurrent treatment of in-stent restenosis.\u003c/em\u003e \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2014, \u003cem\u003e63(\u003c/em\u003e24):2659–2673.\u003c/p\u003e\n\u003cp\u003e2.Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eA randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.\u003c/em\u003e \u003cem\u003eN Engl J Med \u003c/em\u003e2002, \u003cem\u003e346(\u003c/em\u003e23):1773–1780.\u003c/p\u003e\n\u003cp\u003e3.Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003e2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.\u003c/em\u003e \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2016, \u003cem\u003e68(\u003c/em\u003e10):1082–1115.\u003c/p\u003e\n\u003cp\u003e4.Bonaa KH, Mannsverk J, Wiseth R, Aaberge L, Myreng Y, Nygard O, Nilsen DW, Klow NE, Uchto M, Trovik T\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eDrug-Eluting or Bare-Metal Stents for Coronary Artery Disease.\u003c/em\u003e \u003cem\u003eN Engl J Med \u003c/em\u003e2016, \u003cem\u003e375(\u003c/em\u003e13):1242–1252.\u003c/p\u003e\n\u003cp\u003e5.Morice MC, Urban P, Greene S, Schuler G, Chevalier B: \u003cem\u003eWhy are we still using coronary bare-metal stents?\u003c/em\u003e \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2013, \u003cem\u003e61(\u003c/em\u003e10):1122–1123.\u003c/p\u003e\n\u003cp\u003e6.Dehmer GJ, Weaver D, Roe MT, Milford-Beland S, Fitzgerald S, Hermann A, Messenger J, Moussa I, Garratt K, Rumsfeld J\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eA contemporary view of diagnostic cardiac catheterization and percutaneous coronary intervention in the United States: a report from the CathPCI Registry of the National Cardiovascular Data Registry, 2010 through June 2011.\u003c/em\u003e \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2012, \u003cem\u003e60(\u003c/em\u003e20):2017–2031.\u003c/p\u003e\n\u003cp\u003e7.Versaci F, Gaspardone A, Tomai F, Ribichini F, Russo P, Proietti I, Ghini AS, Ferrero V, Chiariello L, Gioffrè PA\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eImmunosuppressive Therapy for the Prevention of Restenosis after Coronary Artery Stent Implantation (IMPRESS Study).\u003c/em\u003e \u003cem\u003eJournal of the american college of cardiology \u003c/em\u003e2002, \u003cem\u003e40(\u003c/em\u003e11):1935‐1942.\u003c/p\u003e\n\u003cp\u003e8.Hausleiter J, Kastrati A, Mehilli J, Vogeser M, Zohlnhöfer D, Schühlen H, Goos C, Pache J, Dotzer F, Pogatsa-Murray G\u003cem\u003e et al:\u003c/em\u003e \u003cem\u003eRandomized, double-blind, placebo-controlled trial of oral sirolimus for restenosis prevention in patients with in-stent restenosis: the Oral Sirolimus to Inhibit Recurrent In-stent Stenosis (OSIRIS) trial.\u003c/em\u003e \u003cem\u003eCirculation \u003c/em\u003e2004, \u003cem\u003e110(\u003c/em\u003e7):790‐795.\u003c/p\u003e\n\u003cp\u003e9.Ribichini F, Tomai F, Ferrero V, Versaci F, Boccuzzi G, Proietti I, Prati F, Crea F, Vassanelli C: \u003cem\u003eImmunosuppressive oral prednisone after percutaneous interventions in patients with multi-vessel coronary artery disease. 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patients included in the meta-analysis stratified by trial.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; margin-left: 4.8pt; margin-right: 4.8pt;\" width=\"100%\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 34.1pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eTrial\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eN\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eAge\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003e, years\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eMales (%)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eACS (%)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eLAD (%) #\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eRD pre,\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003e\u0026nbsp;mm\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"21%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eIST method\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eSurveillance angiography (%)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 34.1pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eMean follow up time, months\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 2.2pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eLee \u003cem\u003eet al.\u003csup\u003e14\u003c/sup\u003e\u003c/em\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e140\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e58(9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e66\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e61\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e46\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e3.41(0.38)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003ebefore PCI: 1g methylprednisolone i.v.\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e91\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 2.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e10.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 3.2pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eIMPRESS\u003csup\u003e7\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e83\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e64(9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e83\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e52\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e3.10(0.05)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e72h to 45 days after PCI: prednisone oral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e98\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 3.2pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eOSIRIS\u003csup\u003e8\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e300\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e65(9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e78\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e49\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e2.59(0.52)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e48h prior to 7 days after PCI: sirolimus oral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e86\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 3.2pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eORAR II\u003csup\u003e10\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e100\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e65(9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e91\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e65\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e47\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e2.94(0.56)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e2.7h prior to 14 days after PCI: sirolimus oral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e87\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.0pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eStojkovic \u003cem\u003eet al.\u003csup\u003e12\u003c/sup\u003e\u003c/em\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e80\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e58(10)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e70\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e54\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e41\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e2.59(0.44)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003epost-procedure to 30 days: sirolimus oral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e90\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.0pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e6.8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 16.65pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eCernigliaro \u003cem\u003eet al.\u003csup\u003e11\u003c/sup\u003e\u003c/em\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e108\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e63(11)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e84\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e68\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e76\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e2.93(0.72)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003epost-procedure to 30 days: sirolimus oral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e96\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 16.65pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 5.75pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eNamdari \u003cem\u003eet al.\u003csup\u003e15\u003c/sup\u003e\u003c/em\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e200\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e60(7)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e56\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eN/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eN/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eN/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003etwo doses at 2-week interval: prednisolone i.m.\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e100\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.75pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eN/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 3.2pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eCEREA -DES\u003csup\u003e13\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e250\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e64(9)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e84\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e61\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e62\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e3.15(0.53)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003epost-procedure to 40 days: prednisone oral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eN/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 3.2pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 5.05pt;\"\u003e\n\u003ctd style=\"width: 12.18%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"12%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cstrong\u003e\u003cspan style=\"line-height: 200%;\"\u003eSSTARS\u003csup\u003e16\u003c/sup\u003e\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 5.0%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"5%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e315\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.16%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e60\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 7.06%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"7%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e85\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.06%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 6.0%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"6%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eN/A\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 10.08%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"10%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e3.18(0.42)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 21.2%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"21%\"\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cspan style=\"line-height: 200%;\"\u003e6h prior to 28 days after PCI: \u003c/span\u003e\u003cspan style=\"line-height: 200%;\"\u003eprednisolone oral\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 13.12%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"13%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e91\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 12.12%; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 5.05pt;\" width=\"12%\"\u003e\n\u003cp style=\"text-align: center; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eData are mean (SD), unless otherwise indicated. # variables counted by patient.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u003cspan style=\"color: #000000; font-size: 10pt;\"\u003e\u003cspan style=\"line-height: 200%;\"\u003eACS: acute coronary syndrome; IST: immunosuppressive therapy; i.v.: intravenous; i.m.: intramuscular; LAD: left anterior descending artery; PCI: percutaneous coronary intervention; RD pre: reference diameter before intervention; N/A: not applicable. Trial acronyms: IMPRESS: Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Stent Implantation; OSIRIS: Oral Sirolimus to Inhibit Recurrent In-stent Stenosis; ORAR: Oral Rapamycin in Argentina; CEREA-DES: Cortisone plus BMS or DES versus BMS alone to eliminate restenosis; SSTARS:\u003c/span\u003e \u003cspan style=\"line-height: 200%;\"\u003eSTeroids and Stents Against Re-Stenosis.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"line-height: 200%;\"\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"immunosuppressive therapy, restenosis, bare-metal stents , meta-analysis","lastPublishedDoi":"10.21203/rs.2.16970/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.16970/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Previous studies revealed controversial results regarding the prevention of in-stent restenosis after coronary bare-metal stents (BMS) placement with systemic administration of immunosuppressive drugs. We therefore conducted a meta-analysis to investigate the role played by immunosuppressive therapy (IST) in reducing both in-stent restenosis and adverse clinical events after BMS implantation. \u003c/p\u003e\u003cp\u003eMethods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases for randomized, controlled studies that investigated the therapeutic effects of IST after BMS insertions. Endpoints assessed were: (1) angiographic restenosis by the end of at least 6 months of follow-up; (2) target vessel revascularization (TVR); and (3) risk of major adverse cardiovascular events (MACE). MACE was defined as death, myocardial infarction and TVR. \u003c/p\u003e\u003cp\u003eResults: Nine randomized, controlled trials including 1576 patients (mean age 62 years; follow-up of 6-12 months) were included in this analysis. Meta-analysis showed periprocedural IST + BMS significantly reduced in-stent restenosis as compared to BMS alone (RR: 0.59 [0.39-0.90], P = 0.01). In particular, IST reduced restenosis in high-risk patients (defined as patients with mean reference diameter \u0026lt; 3.0 mm or high periprocedural C-reactive protein level) (RR: 0.34 [0.15,0.74], P = 0.006) rather than in low-risk patients ( P for interaction = 0.06). Similarly, IST also reduced the risk of MACE (RR: 0.63 [0.50-0.80], P \u0026lt; 0.01) and TVR (RR: 0.57 [0.33-0.97], P = 0.04). \u003c/p\u003e\u003cp\u003eConclusions: Periprocedural IST reduces the risk of angiographic restenosis, TVR and MACE in patients with BMS implantation. The advantage of IST is driven mainly by a lower risk of in-stent restenosis in high-risk patients. Key words: immunosuppressive therapy, restenosis, bare-metal stents , meta-analysis\u003c/p\u003e","manuscriptTitle":"Immunosuppressive Therapy for Restenosis Prevention after Coronary Bare-Metal Stent Implantation -A Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2019-11-09 01:10:51","doi":"10.21203/rs.2.16970/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9edb8530-22d6-4669-a7d1-91e6348984a4","owner":[],"postedDate":"November 9th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":35629,"name":"Cardiothoracic Surgery"}],"tags":[],"updatedAt":"","versionOfRecord":[],"versionCreatedAt":"2019-11-09 01:10:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7607","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-7607","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}