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Intravascular ultrasound–guided vs angiography-guided drug-eluting stent implantation in complex coronary lesions: Meta-analysis of randomized trials
Intravascular Ultrasound-guided versus Angiography-guided Drug-eluting Stent Implantation in Complex Coronary Lesions: Meta-analysis of randomized trials Chirag Bavishi MD, MPH, Partha Sardar MD, Saurav Chatterjee MD, Abdur Rahman Khan MD, Arpit Shah MD, Sameer Ather MD, PhD, Pedro A. Lemos MD, Pedro Moreno MD, Gregg W Stone MD PII: DOI: Reference:
S0002-8703(16)30230-7 doi: 10.1016/j.ahj.2016.10.008 YMHJ 5303
To appear in:
American Heart Journal
Received date: Accepted date:
30 July 2016 15 October 2016
Please cite this article as: Bavishi Chirag, Sardar Partha, Chatterjee Saurav, Khan Abdur Rahman, Shah Arpit, Ather Sameer, Lemos Pedro A., Moreno Pedro, Stone Gregg W, Intravascular Ultrasound-guided versus Angiography-guided Drug-eluting Stent Implantation in Complex Coronary Lesions: Meta-analysis of randomized trials, American Heart Journal (2016), doi: 10.1016/j.ahj.2016.10.008
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ACCEPTED MANUSCRIPT Intravascular Ultrasound-guided versus Angiography-guided Drug-eluting Stent Implantation in Complex Coronary Lesions: Meta-analysis of
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randomized trials
Chirag Bavishi*, MD, MPH, Partha Sardar, MD†, Saurav Chatterjee*, MD, Abdur Rahman
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Khan+, MD, Arpit Shah*, MD, Sameer Ather¶, MD, PhD, Pedro A. Lemosκ, MD, Pedro
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Moreno*, MD, Gregg W Stone, MD║
Mount Sinai St. Luke's & Mount Sinai West Hospitals, New York, NY; †University of Utah,
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Salt Lake City, Utah; +University of Louisville, Louisville, KY; ¶University of Alabama at
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Birmingham, Birmingham, AL;κHeart Institute (InCor), University of Sao Paulo Medical School,
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Sao Paulo, Brazil; ║Columbia University Medical Center, New York-Presbyterian Hospital and
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the Cardiovascular Research Foundation, New York, NY
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Short Title: IVUS versus angiography-guided stenting
Word count (abstract, manuscript text, references, legend): 4,035 Conflicts of Interests/Disclosures: None Funding: None
Corresponding author: Gregg W. Stone, MD 1700 Broadway, 8th Floor New York, NY 10019, USA Tel: +1 646-434-4131 Fax: +1 646-434-4715 Email: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT Background: The relative outcomes of IVUS-guided PCI compared to angiography-guided PCI
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with DES in complex lesions has not been established. We sought to compare the efficacy and
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safety of intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) with angiography-guided PCI in patients with complex coronary lesions treated with drug-eluting
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stents (DES).
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Methods: Electronic databases were searched to identify all randomized trials comparing IVUSguided vs. angiography-guided DES implantation. We evaluated major adverse cardiac events
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(MACE), all-cause and cardiovascular death, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR) and stent thrombosis outcomes at
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the longest reported follow-up. Random effects modeling was used to calculate pooled relative
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risk (RR) and 95% confidence intervals (CI). Results: Eight trials comprising 3,276 patients (1,635 IVUS-guided and 1,641 angiography-
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guided) enrolling only patients with complex lesions were included. Mean follow-up was 1.4 ±
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0.5 years. Compared to angiography-guided PCI, patients undergoing IVUS-guided PCI had significantly lower MACE (RR: 0.64, 95% CI: 0.51-0.80, p=0.0001), TLR (RR: 0.62, 95% CI: 0.45–0.86, p=0.004) and TVR (RR: 0.60, 95% CI: 0.42–0.87, p=0.007). There were no significant differences for stent thrombosis, cardiovascular death or all-cause death. In metaregression analysis, IVUS-guided PCI was of greatest benefit in reducing MACE in patients with acute coronary syndromes, diabetes and long lesions. Conclusions: The present meta-analysis demonstrates a significant reduction in MACE, TVR and TLR with IVUS-guided DES implantation in complex coronary lesions.
ACCEPTED MANUSCRIPT Key words: intravascular ultrasound, angiography, percutaneous coronary intervention, drug-
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eluting stent, outcomes
ACCEPTED MANUSCRIPT Introduction Drug-eluting stents (DES) are widely used in patients undergoing percutaneous coronary
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intervention (PCI) (1), and significantly reduce restenosis and subsequent revascularization
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compared to bare metal stents (2-4). Nonetheless, stent thrombosis and restenosis still occur (especially in complex lesions), and are associated with increased mortality (5,6). In addition to
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clinical and patient-related factors, suboptimal stent deployment with underexpansion and
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residual edge disease and dissections contributes to the occurrence of subsequent events (7,8). Intravascular ultrasound (IVUS) provides information about reference vessel dimensions
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and lesion characteristics such as severity, length and morphology that are poorly appreciated by coronary angiography. As such, IVUS may be used to optimize stent deployment and identify
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stent-related complications (9). In the bare metal stent era, randomized clinical trials (RCTs) and
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observational studies demonstrated improved clinical outcomes with IVUS-guided compared to angiography-guided PCI (10-12). Nonetheless, IVUS is presently used infrequently in the US
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and Europe to guide PCI procedures (13,14), in part because of a paucity of RCT data in the
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contemporary DES era. During the past year, three randomized trials evaluating IVUS-guided versus angiography-guided coronary DES implantation were published (15-17), although none were adequately powered for clinical endpoints. We therefore performed a systematic review and meta-analysis of all available randomized trials to investigate the efficacy of routine IVUSguided PCI compared to angiography-guided PCI for DES implantation.
Methods Search strategy. We performed a systematic search, without language restriction, using PUBMED, EMBASE, SCOPUS, google scholar and ClinicalTrials.gov from inception to June,
ACCEPTED MANUSCRIPT 2016 for RCTs comparing IVUS-guided PCI with angiography-guided PCI with DES implantation. We also searched conference proceedings of Transcatheter Cardiovascular
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Therapeutics, EuroPCR, Society of Cardiovascular Angiography and Intervention, American
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College of Cardiology, American Heart Association, and European Society of Cardiology from the last 10 years. Furthermore, we performed manual searches through the reference lists of
intravascular ultrasound,
IVUS, IVUS-guided, angiography,
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following MeSH terms:
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studies, reviews and pertinent meta-analyses on this topic. The search keywords included the
angiography-guided, percutaneous coronary intervention, PCI, stenting (Supplement Table 1).
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Study selection and eligibility criteria. Studies were included if they met the following criteria: (1) RCTs comparing IVUS-guided versus angiography-guided PCI; (2) DES
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implantation only, (3) data on cardiac outcomes provided; and (4) at least 1 year of follow-up.
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For the purpose of this systematic review, we focused on complex coronary lesions, defined as long coronary lesions or those requiring ≥4 stents, small vessels, bifurcation lesions, chronic total
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occlusions, and other complex lesions as defined by the individual trials. Two physician-
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reviewers (CB and PS) independently and in duplicate performed the literature search, reviewed the originally identified titles and abstracts and selected studies for meta-analysis based on the inclusion criteria. Any divergence was resolved by consensus. Quality of the included studies and assessment of trial bias risk was assessed for the domains suggested by the Cochrane collaboration (18), emphasizing sequence generation, allocation concealment, blinding, outcomes assessment, and selective reporting. Data extraction and outcomes. Two independent reviewers (CB and ARK) extracted the following data from individual studies: first author, year of publication, study characteristics, sample size, patient baseline characteristics, follow-up duration, and clinical outcomes in the
ACCEPTED MANUSCRIPT angiography-guided and IVUS-guided groups. We evalauted the following outcomes: (1) allcause and cardiovascular death; (2) major adverse cardiac events (MACE); (3) myocardial
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infarction (MI); (4) target lesion revascularisation (TLR); (5) target vessel revascularisation
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(TVR); and (6) stent thrombosis. The definition of MACE and MI differed slightly across studies, and the trial-specific definitions for each were used. Stent thrombosis was defined as
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definite or probable stent thrombosis according to the Academic Research Consortium criteria
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(19).
Statistical analysis. Statistical analysis was performed per recommendations from the
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Cochrane Collaboration and the Preferred Reporting Items for Systematic reviews and Metaanalyses (PRISMA) guidelines (20,21). Analysis was performed on an intention-to-treat basis.
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Considering that the heterogeneity of the included trials might influence the treatment effects, we
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used a random-effects model as the primary analysis to examine relative risks (RR) and confidence intervals (CI) (22). The results were confirmed by a fixed effects model to avoid
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small studies being overly weighted. Heterogeneity was assessed using Higgins and Thompson’s
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I2 statistic. I2 is the proportion of total variation observed between the trials attributable to differences between trials rather than sampling error, with I2 values of <25%, 25%-75%, and >75% corresponding to low, moderate and high levels of heterogeneity, respectively (23). Treatment effects were further explored using meta-regression and sensitivity analysis. Publication bias was visually estimated by funnel plots and Begg and Mazumdar’s rank correlation test (24). A 2-tailed p <0.05 was considered statistically significant for all analyses. Statistical analysis was performed using Stata 11 (Stata Corp., College Station, Texas) and RevMan v5.02 (Nordic Cochrane Center).
ACCEPTED MANUSCRIPT Funding. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing
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of the paper and its final contents. None of the authors have any conflict of interest.
Results
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Trials and patients. Based on our eligibity criteria, 8 RCTs (15-17,25-29) of IVUS-
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guided vs. angiography-guided DES implantation were identified and included in the final analysis (Figure 1). Of 3,276 enrolled patients, 1,635 were randomized to IVUS-guided PCI and
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1,641 patients were randomized to angiography-guided PCI. Each trial only enrolled patients with complex lesions. The Study comparing Angiography vs. IVUS-guided stent implantation
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for chronic total occlusion in coronary artery (AIR-CTO) (16) and Chronic Total Occlusion
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InterVention with drUg-eluting Stents guided by IVUS (CTO-IVUS) (17) included patients with chronic total occlusions (CTO); the Impact of Intravascular Ultrasound Guidance on Outcomes
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of Xience Prime Stents in Long Lesions (IVUS-XPL) (15) and Real Safety and Efficacy of a 3-
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Month Dual Antiplatelet Therapy Following Zotarolimus-Eluting Stents Implantation (RESET) (27) trials included patients with long coronary lesions, while the study by Zhang et al (29) included patients with small vessel lesions; the Angiography Versus IVUS Optimization (AVIO) (25) trial included patients with long lesions, CTOs, bifurcation lesions, small vessels and patients requiring ≥4 stents; the Long-Term Health Outcome andMortality Evaluation After Invasive Coronary Treatment Using Drug Eluting Stents with or without the IVUS Guidance (HOME DES IVUS) (26) trials included patients with either complex coronary lesions or characteristics; and Tan et al (28) studied patients with unprotected left main coronary artery intervention. The exclusion criteria in trials is presented in Supplement Table 2. Characteristics
ACCEPTED MANUSCRIPT of the included studies are shown in Table 1. On quality assessment all the trials, except Tan et al (28) and Zhang et al(29), had low-risk of bias (Supplement Table 3). Three trials (13,20,22) used
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first-generation DES (sirolimus-eluting and paclitaxel-eluting) either predominately or
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exclusively, three trials (15,17,27) used newer generation DES (everolimus-eluting, zotarolimuseluting, and biolimus-eluting), and two trials (25,29) did not provide information on the type of
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DES. The mean follow-up duration was 1.4 ± 0.5 years. Baseline clinical and quantitative
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coronary angiographic (QCA) data are presented in Tables 2 and 3. Clinical results. The results of the random effects meta-analysis appear in Figures 2 and
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3. All 8 trials reported MACE data. IVUS-guided PCI significantly decreased MACE by 36% when compared to angiography-guided PCI (6.5% vs. 10.5%; RR: 0.64, 95% CI: 0.51 - 0.80,
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p=0.0001). No statistical heterogeneity was noted among the included studies (I2=0%, p=0.46).
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Four trials (16,17,26,27) reported rates of all-cause death. There was no significant difference in rates of all-cause death between IVUS-guided and angiography-guided PCI (2.0% vs. 2.0%, RR:
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1.00, 95% CI: 0.48 -2.09, p=0.99). No statistical heterogeneity was present (I2 =0%, p=0.87).
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Seven trials (15-17,25,27-29) reported cardiovascular death data. IVUS-guided PCI showed a trend towards decreased cardiovascular death compared to angiography-guided group (0.5% vs. 1.2%; RR: 0.51, 95% CI: 0.23 – 1.12, p=0.09). No statistical heterogeneity was present (I2=0%, p=0.96). All trials reported MI data. No significant difference in the rates of MI was found between the two groups (2.0% vs. 2.4%; RR: 0.90, 95% CI: 0.58 – 1.41, p=0.65). There was no evidence of statistical heterogeneity (I2=0%, p=0.65). Five trials (16,17,25,27,29) reported TVR data, 6 trials (15-17,25,26,28) reported TLR data and 7 trials reported stent thrombosis data. IVUS-guided PCI significantly reduced TVR (5.5% vs. 9.2%; RR: 0.60, 95% CI: 0.42 – 0.87,
ACCEPTED MANUSCRIPT p=0.007) and TLR (4.1% vs. 6.6%; RR: 0.62, 95% CI: 0.45 – 0.86, p=0.004). The reduction in stent thrombosis with IVUS-guidance was not statistically significant (0.6% vs. 1.3%; RR: 0.57,
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95% CI: 0.26 – 1.23, p=0.15). No evidence of statistical heterogeneity was noted among studies
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with resepct to TVR (I2=0%, p=0.87), TLR (I2=0%, p=0.84), or stent thrombosis (I2=0%, p=0.65).
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Sensitivity analysis, publication bias assessment, and meta-regression. Sensitivity
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analysis using fixed effect models yielded largely similar results (Supplement Table 4). Moreover, after exclusion of the Tan et al and Zhang et al trials (potentially high-bias risk
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studies) the results remained unchanged (Supplement Table 5). No publication bias was found either on inspection of funnel plots (Supplement Figure 2) or on Begg’s rank correlation test (p
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for MACE=0.17; p for all-cause death = 0.73; p for cardiovascular death=0.30; p for MI=0.46; p
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for TVR=0.09; p for TLR=0.99 and p for stent thrombosis=0.99). Meta-regression analysis showed a greater magnitude of benefit of IVUS-guided PCI compared to angiography-guided
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PCI for MACE in trials with higher proportion of patients with acute coronary syndrome
Discussion
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(p=0.02), diabetes (p=0.01) and with longer lesion length (p=0.01) (Supplement Figure 1).
The main findings of the present meta-analysis are that in patients with complex lesions undergoing PCI with DES, IVUS-guidance compared to angiography-guidance resulted in: (1) significantly reduced rates of MACE, TLR and TVR at mean 1.4 year follow-up; (2) nonsignificantly different rates of stent thrombosis, MI and death; and (3) maximal benefit in patients with acute coronary syndromes, diabetes and long lesions.
ACCEPTED MANUSCRIPT The present report extends the results from prior meta-analyses of IVUS-guided vs. angiography-guided PCI for DES implantation, finding some similarities but other notable
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differences. Zhang et al performed a meta-analysis of 1 RCT and 10 observational studies,
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reporting significantly lower rates of MACE, death and stent thrombosis with IVUS-guided PCI (11). The rates of MI, TVR and TLR were comparable in both groups. In another meta-analysis
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by Jang et al which included 3 RCTs and 11 observational studies, IVUS-guided PCI was
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associated with significant reductions in MACE, all-cause mortality, MI, TVR and stent thrombosis (10). Of note, repeat revascularization rates (TVR and TLR) were comparable in the
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two groups in studies when analyzed using propensity-matching methodology, and significant heterogeneity was present between studies. In our analysis, which is the largest meta-analysis to
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date and was restricted to RCTs of DES in complex lesions, IVUS-guided PCI was associated
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with reduced rates of MACE by 35%, principally mediated by 38% and 37% reductions in TLR and TVR respectively. In contrast, while the rates of stent thrombosis and cardiovascular death
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were numerically lower in the IVUS-guided compared to the angiography-guided groups, these
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differences were not statistically significant, and rates of MI were comparable with the two approaches. While these data strongly support the role of IVUS-guidance to improve the efficacy of DES implantation, further studies are warranted to determine whether IVUS enhances the safety (MI, stent thrombosis and death) of PCI in the contemporary DES era. The benefits of IVUS in reducing the need for subsequent revascularization likely accrue from its ability to facilitate improved stent expansion and to minimize geographic miss and undetected edge dissections, collectively the greatest correlates of restenosis after bare metal stent and DES implantation (8). IVUS provides precise plaque, vessel and lumen measurements aiding in appropriate stent sizing. A smaller stent area has consistently been shown to be the
ACCEPTED MANUSCRIPT strongest predictor of both restenosis and early and late stent thrombosis (30,31). In this regard the minimum lumen diameter was numerically larger with IVUS-guided compared to
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angiography-guided PCI in 7 of 8 trials (15-17,25,26,28,29), and the % diameter stenosis was
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numerically lower in all 6 trials in which this data was reported (15-17,25,26,29), consistent with enhanced stent optimization. In addition, IVUS-guided PCI helps in detection of stent-related
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complications such as incomplete stent apposition, incomplete lesion coverage, edge dissections,
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stent fracture, tissue protrusion, and residual thrombus, findings that are often inapparent by angiography.
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It should be emphasized that all the trials in the present meta-analysis were performed in patients with complex lesion or patient characteristics. PCI of complex lesions has been
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associated with worse short-term and long-term outcomes (32). In such interventions, IVUS-
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guided PCI may guide not only the stent deployment but also the selection of treatment approaches according to lesion morphology, such as direct stenting, plaque modification with
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rotational atherectomy, etc. which may improve early and late outcomes. However, it is
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uncertain if similar benefit with IVUS-guidance will be observed in low-risk patients or lesions in whom the long-term prognosis is excellent with contemporary DES. Currently, the American College of Cardiology Foundation/ American Heart Associate PCI guidelines (33) recommend IVUS as a potential diagnostic tool for the assessment of angiographically indeterminate left main stenosis (class IIa, level of evidence B), cardiac allograft vasculopathy (IIa, B), evaluation of the mechanism of in-stent restenosis (IIa, C), assessment of intermediate non–left main coronary stenoses (IIb, B), and for guidance of coronary stent implantation, particularly in cases of left main stenting (IIb, B). The lack of any class I guideline recommendations for IVUS-
ACCEPTED MANUSCRIPT guidance emphasizes the need for additional adequately powered RCTs to evaluate the role of routine IVUS-guided PCI in patients with different risk profiles and lesion morphologies.
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Limitations. The present study has several limitations. First, all the trials enrolled
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patients undergoing complex coronary interventions, limiting the generalizability of the results. Second, in absence of patient-level data, we were unable to adjust our analysis for severity of
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presentation, lesion characteristics, use of various anticoagulants and anti-platelet therapy, or
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different stent types. However, the meta-regression analysis suggested that IVUS-guidance is of greatest benefit in particularly high-risk patients and lesions (acute coronary syndromes, diabetes
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and long lesions). Additional studies are required to determine the utlilty of IVUS-guidance for DES implantation in non-complex lesions. Third, two trials included in our analysis (26,28) were
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single-center studies which may introduce some degree of institutional or operator bias (although
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no statistical heterogeneity was observed between studies for any of the endpoints). Fourth, the IVUS criteria for stent optimization after PCI varied among trials, (Supplement Table 6) as did
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the specific definitions for MACE and MI. As such the results of the present study should be
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considered hypothesis-generating. Fifth, all of the trials examining outcomes of IVUS guidance in the DES era have exclusively enrolled high-risk patients and/or lesions. No such trials were broadly inclusive. As a result, whether IVUS guidance of DES implantation in simpler lesions would yield similar results as those found in the present meta-analysis is unknown. Finally, although the present study is the most comprehensive meta-analysis of IVUS-guided vs. angiography-guided PCI with DES to date, we still lack adequate power to determine whether the trends toward reduced stent thrombosis and cardiovascular death are real, again emphasizing the need for future large-scale trials. Such studies should also include a cost-effectiveness component to determine the value of IVUS-guided intervention.
ACCEPTED MANUSCRIPT Conclusions. The present meta-analysis of 8 RCTs and 3,276 patients demonstrated a significant reduction in MACE, TVR and TLR with IVUS-guided compared to angiography-
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guided DES implantation in patients with complex lesions and clinical characterisitics. IVUS use
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to optimize acute stent outcomes should thus strongly be considered when performing PCI in such patients. Additional adequately powered trials would be useful to further define the role of
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IVUS-guided PCI in patients with different risk profiles and lesion morphologies, and to
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determine the optimal IVUS parameters and guidance strategies to maximize event-free survival
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after DES in complex case scenarios.
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2011;58:e44-122.
the use of iodine contrast in percutaneous coronary intervention: the MOZART (Minimizing cOntrast utiliZation With IVUS Guidance in coRonary angioplasTy) randomized controlled trial. JACC Cardiovascular interventions 2014;7:1287-93.
Figure Legends Figure 1. Flowchart for study selection. A systematic search identified randomized trials in which high-risk paitents and/or complex lesions were allocated to DES implnatation with IVUS-
ACCEPTED MANUSCRIPT guidance vs. angiography-guidance. Non-randomized trials were excluded fom this metaanalysis, as were trials in which most of all patients were treated with bare metal stents. The
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stratified by stent type (personal communciation, Pedro Lemos).
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MOZART trial(34) was excluded as DES were used in <10 patients, and randomization was not
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Figure 2. Forest plot of pooled relative risks (95% confidence intervals) for (A) MACE, (B) all-cause death, and (C) cardiovascular death, for IVUS-guided compared to angiography-
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guided PCI with DES. Squares represent the risk ratio of the individual studies; Horizontal
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lines represent the 95% confidence intervals (CI) of the risk ratio. The size of the squares reflects the weight that the corresponding study contributes in the meta-analysis. The diamonds
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represents the pooled risk ratio or the overall effect.
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Figure 3. Forest plot of pooled relative risks (95% confidence intervals) for (A) myocardial
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infarction, (B) target vessel revascularization, (C) target lesion revascularization, and (D) stent thrombosis, for IVUS-guided PCI compared to angiography-guided PCI with DES.
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Other notations as in Figure 2.
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ACCEPTED MANUSCRIPT Table 1. Charateristics of the included trials AVIO 2013
CTO-IVUS 2015
HOME DES IVUS 2010
IVUS-XPL 2015
RESET 2013
Tan et al. 2015
Zhang et al. 2016
Center
Multicenter
Multicenter
Multicenter
Single-center
Multicenter
Multicenter
Single-center
Single-center
Inclusion criteria
CTO
Long lesions (≥28 mm), CTO, bifurcation lesions, small vessels (≤2.5mm), patients requiring ≥4 stents.
CTO
AHA lesion type B2/C, proximal LAD, left main disease, RVD <2.5 mm, lesion length >20 mm, instent restenosis, insulin dependent diabetes mellitus and ACS
Long coronary lesions requiring stent length ≥28 mm with RVD 2.5-4 mm
De novo lesion requiring a stent ≥28 mm in length in a vessel with a distal RVD ≥2.5 mm
Unprotected left main coronary artery stenosis
De novo lesion in a small vessel (diameter 2.25-2.75 mm)
Sample size
230
284
402
210
1400
543
123
84
DES+
DES
ZES/BES
SES, PES
EES
ZES, EES
SES
DES
Clinical FU
24 months
24 months
12 months
18 months
12 months
12 months
24 months
12 months
Primary endpoint
In-stent late lumen loss
Post-procedural in-lumen MLD
Cardiac death
MACE
MACE
MACE
MACE
Post-procedural in-lumen MLD
MACE
Death, MI, TLR, stent thrombosis
Cardiovascular death, MI or TVR
Cardiac death, MI, or TVR
Death, MI, TLR
Cardiac death, target lesion– related MI, or TLR
Cardiovascular death, MI,
Cardiac death, MI, or TLR
Cardiac death, MI, or TVR
NR
NR
Aspirin 300 mg for 1 month, then 100 mg lifelong, clopidogrel 75 mg for 12 months
NR
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Aspirin 100 mg, clopidogrel 75 mg for at least 12 months
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Dual antiplatelet regimen
Aspirin 100 mg lifelong, clopidogrel 75 mg for 6 months
Aspirin 100 mg lifelong, clopidogrel 75 mg for 12 months
stent thrombosis, or TVR
Aspirin 100 mg lifelong, clopidogrel 75 mg for 3-12 months*
* 3-month duration following E-ZES implantation versus 12-month duration following EES implantation, +predominatly first generation DES (76.1%). ACS: acute coronary syndrome, AHA: American heart association, CTO: chronic total occlusion, LAD: left anterior descending, DES: drug-eluting stents, BES: biolimus-eluting stent, PES: paclitaxel-eluting stent, SES: sirolimus-eluting stent, EES: everolimus-eluting stent, ZES: zotarolimus-eluting stent, MACE: major adverse cardiac events, MI: myocardial infarction, MLD: minimum lumen diameter, RVD: reference vessel diameter, TLR: target lesion revascularization, TVR: target vessel revascularization, NR: not reported.
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Stent type
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Year
AIR-CTO 2015
ACCEPTED MANUSCRIPT Table 2. Patient characteristics CTO IVUS
67/66
64/64
61/61
HOME DES IVUS 59/60
Male, %
89/80
82/77
81/81
73/71
Diabetes, %
30/27
24/27
35/34
42/45
Hypertension,
75/70
70/67
63/64
67/61
22/28
70/77
NR
39/39
35/31
35/34
21/30
NR
Age, mean
%
CABG, %
3/4
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Previous
77/76
63/60
32/30
34/30
NR
65/63
61/66
41/47
64/60
67/65
61/62
NR
48/60
40/35
22/26
22/17
44/47
52/52
8/8
37/32
5/4
1/3
16/21
NR
NR
15/16
17/14
11/10
NR
NR
NR
NR
2/3
14/10
3/2
NR
NR
NR
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20/21
63/64
36/37
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Previous PCI,
64/64
50/60
smoker, %
%
Zhang et al.
62/69
%
Previous MI,
Tan et al.
66/55
%
Current
RESET
69/69
years
Dyslipidemia,
IVUSXPL
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AVIO
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AIRCTO
ACS, %
29/24
30/26
NR
72/60
49/49
47/49
70/66
NR
LVEF, %
55/56
55/56
NR
NR
63/62
NR
55/55
58/57
Data are presented as IVUS-guided / angiography-guided. ACS: acute coronary syndrome which includes acute MI and/or unstable angina, CABG: coronary atery bypass surgery, LVEF: left ventricular ejection fraction, MI: myocardial infarction, NR: not reported, PCI: percutaneous coronary intervention.
ACCEPTED MANUSCRIPT Table 3. Angiographic and procedural characteristics CTO IVUS
LAD, %
44/37
53/49
42/47
HOME DES IVUS 56/54
LCX, %
21/15
NR
14/16
11/15
RCA, %
35/46
NR
44/37
29/24
LM, %
0/3
NR
0/0
3/4
Multivessel disease, %
49/57
NR
39/31
Preprocedural RVD, mm
2.65±0.37/ 2.60±0.34
2.67±0.46/ 2.62±0.41
2.69±0.44/ 2.64±0.55
Lesion length, mm
29.0±17.4/ 30.6±18.7
27.4±15.9/ 25.5±15.0
MLD, mm
NR
0.76±0.46/ 0.65±0.45
Baseline stenosis, %
100/100
71.6±15.8/ 75.5±16.1
Stent number
1.6±0.9/ 1.5±0.8
IVUSXPL 65/60
RESET
T
AVIO
62/68
RI P
AIRCTO
Tan et al.
Zhang et al.
NR
48/52
15/13
NR
49/51
21/25
23/20
NR
56/44
0/0
0/0
100/100
0/0
31/33
41/38
66/63
NR
3.17±0.43/ 2.95±0.34
2.89±0.45/ 2.85±0.45
2.82/2.80*
NR
2.40±0.23/ 2.39±0.27
18.1±7.3/ 17.6±6.7
34.7±10.8/ 35.2±10.5
29.6/30.6*
NR
17.0±4.2/ 15.1±5.5
NR
1.1±0.4/ 0.97±0.36
0.83±0.42/ 0.82±0.43
0.95/0.93*
1.90±0.22/ 1.92±0.21
0.91±0.3/ 0.90±0.31
NR
82.3±7.6/ 79.2±9.3
71.1±14.3/ 71.4±14.4
NR
NR
77.8±9.1/ 77.8±8.5
NR
1.7±0.8/ 1.6±0.7
1.3/1.3
1.3±0.5/ 1.3±0.5
NR
NR
NR
3.05±0.46/ 2.86±0.37
2.95±0.38/ 2.86±0.36
2.91±0.52/ 2.85±0.41
NR
NR
NR
3.43±0.09/ 3.44±0.12
2.64±0.25/ 2.45±0.20
55±23/ 52±25
23.9±6.74/ 23.2±6.51
43.6±18.7/ 41.5±17.6
23.6/22.1
39.3±13.1/ 39.2±12.3
32.4/32.3*
21.5±6.4/ 18.2±4.9
26.1±4.5/ 23.3±5.8
Postprocedure MLD, mm
2.62±0.45/ 2.40±0.47
2.55±0.46/ 2.39±0.42
2.64±0.35/ 2.56±0.41
2.94±0.31/ 2.87±0.24
2.64±0.42/ 2.56±0.39
2.55/2.55*
3.44±0.12/ 3.43±0.09
2.77±0.19/ 2.53±0.21
Post procedure
10.9±5.7/ 13.8±10.1
13.9±7.3/ 15.5±7.9
9.0±9.8/ 10.2±10.9
14.6±7.1/ 15.3±6.1
12.8±8.7/ 13.7±8.1
NR
NR
6.7±2.6/ 7.9±2.5
Stent length, mm
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26.8±17.3/ 26.4±17.6
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Stent diameter, mm
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14/15
ACCEPTED MANUSCRIPT diameter stenosis, % Data are presented as IVUS-guided / angiography-guided. *Median values, LAD: left anterior descending artery, LCx: left
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circumflex artery, LM: left main, MLD: minimal lumen diameter, NR: not reported, RCA: right coronary artery, RVD: reference vessel diameter.
S0002-8703(16)30230-7 doi: 10.1016/j.ahj.2016.10.008 YMHJ 5303
To appear in:
American Heart Journal
Received date: Accepted date:
30 July 2016 15 October 2016
Please cite this article as: Bavishi Chirag, Sardar Partha, Chatterjee Saurav, Khan Abdur Rahman, Shah Arpit, Ather Sameer, Lemos Pedro A., Moreno Pedro, Stone Gregg W, Intravascular Ultrasound-guided versus Angiography-guided Drug-eluting Stent Implantation in Complex Coronary Lesions: Meta-analysis of randomized trials, American Heart Journal (2016), doi: 10.1016/j.ahj.2016.10.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Intravascular Ultrasound-guided versus Angiography-guided Drug-eluting Stent Implantation in Complex Coronary Lesions: Meta-analysis of
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randomized trials
Chirag Bavishi*, MD, MPH, Partha Sardar, MD†, Saurav Chatterjee*, MD, Abdur Rahman
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Khan+, MD, Arpit Shah*, MD, Sameer Ather¶, MD, PhD, Pedro A. Lemosκ, MD, Pedro
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Moreno*, MD, Gregg W Stone, MD║
Mount Sinai St. Luke's & Mount Sinai West Hospitals, New York, NY; †University of Utah,
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*
Salt Lake City, Utah; +University of Louisville, Louisville, KY; ¶University of Alabama at
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Birmingham, Birmingham, AL;κHeart Institute (InCor), University of Sao Paulo Medical School,
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Sao Paulo, Brazil; ║Columbia University Medical Center, New York-Presbyterian Hospital and
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the Cardiovascular Research Foundation, New York, NY
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Short Title: IVUS versus angiography-guided stenting
Word count (abstract, manuscript text, references, legend): 4,035 Conflicts of Interests/Disclosures: None Funding: None
Corresponding author: Gregg W. Stone, MD 1700 Broadway, 8th Floor New York, NY 10019, USA Tel: +1 646-434-4131 Fax: +1 646-434-4715 Email: [email protected]
ACCEPTED MANUSCRIPT ABSTRACT Background: The relative outcomes of IVUS-guided PCI compared to angiography-guided PCI
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with DES in complex lesions has not been established. We sought to compare the efficacy and
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safety of intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) with angiography-guided PCI in patients with complex coronary lesions treated with drug-eluting
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stents (DES).
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Methods: Electronic databases were searched to identify all randomized trials comparing IVUSguided vs. angiography-guided DES implantation. We evaluated major adverse cardiac events
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(MACE), all-cause and cardiovascular death, myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR) and stent thrombosis outcomes at
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the longest reported follow-up. Random effects modeling was used to calculate pooled relative
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risk (RR) and 95% confidence intervals (CI). Results: Eight trials comprising 3,276 patients (1,635 IVUS-guided and 1,641 angiography-
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guided) enrolling only patients with complex lesions were included. Mean follow-up was 1.4 ±
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0.5 years. Compared to angiography-guided PCI, patients undergoing IVUS-guided PCI had significantly lower MACE (RR: 0.64, 95% CI: 0.51-0.80, p=0.0001), TLR (RR: 0.62, 95% CI: 0.45–0.86, p=0.004) and TVR (RR: 0.60, 95% CI: 0.42–0.87, p=0.007). There were no significant differences for stent thrombosis, cardiovascular death or all-cause death. In metaregression analysis, IVUS-guided PCI was of greatest benefit in reducing MACE in patients with acute coronary syndromes, diabetes and long lesions. Conclusions: The present meta-analysis demonstrates a significant reduction in MACE, TVR and TLR with IVUS-guided DES implantation in complex coronary lesions.
ACCEPTED MANUSCRIPT Key words: intravascular ultrasound, angiography, percutaneous coronary intervention, drug-
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eluting stent, outcomes
ACCEPTED MANUSCRIPT Introduction Drug-eluting stents (DES) are widely used in patients undergoing percutaneous coronary
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intervention (PCI) (1), and significantly reduce restenosis and subsequent revascularization
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compared to bare metal stents (2-4). Nonetheless, stent thrombosis and restenosis still occur (especially in complex lesions), and are associated with increased mortality (5,6). In addition to
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clinical and patient-related factors, suboptimal stent deployment with underexpansion and
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residual edge disease and dissections contributes to the occurrence of subsequent events (7,8). Intravascular ultrasound (IVUS) provides information about reference vessel dimensions
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and lesion characteristics such as severity, length and morphology that are poorly appreciated by coronary angiography. As such, IVUS may be used to optimize stent deployment and identify
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stent-related complications (9). In the bare metal stent era, randomized clinical trials (RCTs) and
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observational studies demonstrated improved clinical outcomes with IVUS-guided compared to angiography-guided PCI (10-12). Nonetheless, IVUS is presently used infrequently in the US
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and Europe to guide PCI procedures (13,14), in part because of a paucity of RCT data in the
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contemporary DES era. During the past year, three randomized trials evaluating IVUS-guided versus angiography-guided coronary DES implantation were published (15-17), although none were adequately powered for clinical endpoints. We therefore performed a systematic review and meta-analysis of all available randomized trials to investigate the efficacy of routine IVUSguided PCI compared to angiography-guided PCI for DES implantation.
Methods Search strategy. We performed a systematic search, without language restriction, using PUBMED, EMBASE, SCOPUS, google scholar and ClinicalTrials.gov from inception to June,
ACCEPTED MANUSCRIPT 2016 for RCTs comparing IVUS-guided PCI with angiography-guided PCI with DES implantation. We also searched conference proceedings of Transcatheter Cardiovascular
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Therapeutics, EuroPCR, Society of Cardiovascular Angiography and Intervention, American
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College of Cardiology, American Heart Association, and European Society of Cardiology from the last 10 years. Furthermore, we performed manual searches through the reference lists of
intravascular ultrasound,
IVUS, IVUS-guided, angiography,
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following MeSH terms:
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studies, reviews and pertinent meta-analyses on this topic. The search keywords included the
angiography-guided, percutaneous coronary intervention, PCI, stenting (Supplement Table 1).
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Study selection and eligibility criteria. Studies were included if they met the following criteria: (1) RCTs comparing IVUS-guided versus angiography-guided PCI; (2) DES
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implantation only, (3) data on cardiac outcomes provided; and (4) at least 1 year of follow-up.
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For the purpose of this systematic review, we focused on complex coronary lesions, defined as long coronary lesions or those requiring ≥4 stents, small vessels, bifurcation lesions, chronic total
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occlusions, and other complex lesions as defined by the individual trials. Two physician-
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reviewers (CB and PS) independently and in duplicate performed the literature search, reviewed the originally identified titles and abstracts and selected studies for meta-analysis based on the inclusion criteria. Any divergence was resolved by consensus. Quality of the included studies and assessment of trial bias risk was assessed for the domains suggested by the Cochrane collaboration (18), emphasizing sequence generation, allocation concealment, blinding, outcomes assessment, and selective reporting. Data extraction and outcomes. Two independent reviewers (CB and ARK) extracted the following data from individual studies: first author, year of publication, study characteristics, sample size, patient baseline characteristics, follow-up duration, and clinical outcomes in the
ACCEPTED MANUSCRIPT angiography-guided and IVUS-guided groups. We evalauted the following outcomes: (1) allcause and cardiovascular death; (2) major adverse cardiac events (MACE); (3) myocardial
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infarction (MI); (4) target lesion revascularisation (TLR); (5) target vessel revascularisation
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(TVR); and (6) stent thrombosis. The definition of MACE and MI differed slightly across studies, and the trial-specific definitions for each were used. Stent thrombosis was defined as
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definite or probable stent thrombosis according to the Academic Research Consortium criteria
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(19).
Statistical analysis. Statistical analysis was performed per recommendations from the
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Cochrane Collaboration and the Preferred Reporting Items for Systematic reviews and Metaanalyses (PRISMA) guidelines (20,21). Analysis was performed on an intention-to-treat basis.
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Considering that the heterogeneity of the included trials might influence the treatment effects, we
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used a random-effects model as the primary analysis to examine relative risks (RR) and confidence intervals (CI) (22). The results were confirmed by a fixed effects model to avoid
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small studies being overly weighted. Heterogeneity was assessed using Higgins and Thompson’s
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I2 statistic. I2 is the proportion of total variation observed between the trials attributable to differences between trials rather than sampling error, with I2 values of <25%, 25%-75%, and >75% corresponding to low, moderate and high levels of heterogeneity, respectively (23). Treatment effects were further explored using meta-regression and sensitivity analysis. Publication bias was visually estimated by funnel plots and Begg and Mazumdar’s rank correlation test (24). A 2-tailed p <0.05 was considered statistically significant for all analyses. Statistical analysis was performed using Stata 11 (Stata Corp., College Station, Texas) and RevMan v5.02 (Nordic Cochrane Center).
ACCEPTED MANUSCRIPT Funding. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing
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of the paper and its final contents. None of the authors have any conflict of interest.
Results
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Trials and patients. Based on our eligibity criteria, 8 RCTs (15-17,25-29) of IVUS-
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guided vs. angiography-guided DES implantation were identified and included in the final analysis (Figure 1). Of 3,276 enrolled patients, 1,635 were randomized to IVUS-guided PCI and
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1,641 patients were randomized to angiography-guided PCI. Each trial only enrolled patients with complex lesions. The Study comparing Angiography vs. IVUS-guided stent implantation
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for chronic total occlusion in coronary artery (AIR-CTO) (16) and Chronic Total Occlusion
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InterVention with drUg-eluting Stents guided by IVUS (CTO-IVUS) (17) included patients with chronic total occlusions (CTO); the Impact of Intravascular Ultrasound Guidance on Outcomes
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of Xience Prime Stents in Long Lesions (IVUS-XPL) (15) and Real Safety and Efficacy of a 3-
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Month Dual Antiplatelet Therapy Following Zotarolimus-Eluting Stents Implantation (RESET) (27) trials included patients with long coronary lesions, while the study by Zhang et al (29) included patients with small vessel lesions; the Angiography Versus IVUS Optimization (AVIO) (25) trial included patients with long lesions, CTOs, bifurcation lesions, small vessels and patients requiring ≥4 stents; the Long-Term Health Outcome andMortality Evaluation After Invasive Coronary Treatment Using Drug Eluting Stents with or without the IVUS Guidance (HOME DES IVUS) (26) trials included patients with either complex coronary lesions or characteristics; and Tan et al (28) studied patients with unprotected left main coronary artery intervention. The exclusion criteria in trials is presented in Supplement Table 2. Characteristics
ACCEPTED MANUSCRIPT of the included studies are shown in Table 1. On quality assessment all the trials, except Tan et al (28) and Zhang et al(29), had low-risk of bias (Supplement Table 3). Three trials (13,20,22) used
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first-generation DES (sirolimus-eluting and paclitaxel-eluting) either predominately or
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exclusively, three trials (15,17,27) used newer generation DES (everolimus-eluting, zotarolimuseluting, and biolimus-eluting), and two trials (25,29) did not provide information on the type of
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DES. The mean follow-up duration was 1.4 ± 0.5 years. Baseline clinical and quantitative
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coronary angiographic (QCA) data are presented in Tables 2 and 3. Clinical results. The results of the random effects meta-analysis appear in Figures 2 and
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3. All 8 trials reported MACE data. IVUS-guided PCI significantly decreased MACE by 36% when compared to angiography-guided PCI (6.5% vs. 10.5%; RR: 0.64, 95% CI: 0.51 - 0.80,
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p=0.0001). No statistical heterogeneity was noted among the included studies (I2=0%, p=0.46).
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Four trials (16,17,26,27) reported rates of all-cause death. There was no significant difference in rates of all-cause death between IVUS-guided and angiography-guided PCI (2.0% vs. 2.0%, RR:
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1.00, 95% CI: 0.48 -2.09, p=0.99). No statistical heterogeneity was present (I2 =0%, p=0.87).
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Seven trials (15-17,25,27-29) reported cardiovascular death data. IVUS-guided PCI showed a trend towards decreased cardiovascular death compared to angiography-guided group (0.5% vs. 1.2%; RR: 0.51, 95% CI: 0.23 – 1.12, p=0.09). No statistical heterogeneity was present (I2=0%, p=0.96). All trials reported MI data. No significant difference in the rates of MI was found between the two groups (2.0% vs. 2.4%; RR: 0.90, 95% CI: 0.58 – 1.41, p=0.65). There was no evidence of statistical heterogeneity (I2=0%, p=0.65). Five trials (16,17,25,27,29) reported TVR data, 6 trials (15-17,25,26,28) reported TLR data and 7 trials reported stent thrombosis data. IVUS-guided PCI significantly reduced TVR (5.5% vs. 9.2%; RR: 0.60, 95% CI: 0.42 – 0.87,
ACCEPTED MANUSCRIPT p=0.007) and TLR (4.1% vs. 6.6%; RR: 0.62, 95% CI: 0.45 – 0.86, p=0.004). The reduction in stent thrombosis with IVUS-guidance was not statistically significant (0.6% vs. 1.3%; RR: 0.57,
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95% CI: 0.26 – 1.23, p=0.15). No evidence of statistical heterogeneity was noted among studies
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with resepct to TVR (I2=0%, p=0.87), TLR (I2=0%, p=0.84), or stent thrombosis (I2=0%, p=0.65).
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Sensitivity analysis, publication bias assessment, and meta-regression. Sensitivity
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analysis using fixed effect models yielded largely similar results (Supplement Table 4). Moreover, after exclusion of the Tan et al and Zhang et al trials (potentially high-bias risk
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studies) the results remained unchanged (Supplement Table 5). No publication bias was found either on inspection of funnel plots (Supplement Figure 2) or on Begg’s rank correlation test (p
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for MACE=0.17; p for all-cause death = 0.73; p for cardiovascular death=0.30; p for MI=0.46; p
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for TVR=0.09; p for TLR=0.99 and p for stent thrombosis=0.99). Meta-regression analysis showed a greater magnitude of benefit of IVUS-guided PCI compared to angiography-guided
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PCI for MACE in trials with higher proportion of patients with acute coronary syndrome
Discussion
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(p=0.02), diabetes (p=0.01) and with longer lesion length (p=0.01) (Supplement Figure 1).
The main findings of the present meta-analysis are that in patients with complex lesions undergoing PCI with DES, IVUS-guidance compared to angiography-guidance resulted in: (1) significantly reduced rates of MACE, TLR and TVR at mean 1.4 year follow-up; (2) nonsignificantly different rates of stent thrombosis, MI and death; and (3) maximal benefit in patients with acute coronary syndromes, diabetes and long lesions.
ACCEPTED MANUSCRIPT The present report extends the results from prior meta-analyses of IVUS-guided vs. angiography-guided PCI for DES implantation, finding some similarities but other notable
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differences. Zhang et al performed a meta-analysis of 1 RCT and 10 observational studies,
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reporting significantly lower rates of MACE, death and stent thrombosis with IVUS-guided PCI (11). The rates of MI, TVR and TLR were comparable in both groups. In another meta-analysis
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by Jang et al which included 3 RCTs and 11 observational studies, IVUS-guided PCI was
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associated with significant reductions in MACE, all-cause mortality, MI, TVR and stent thrombosis (10). Of note, repeat revascularization rates (TVR and TLR) were comparable in the
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two groups in studies when analyzed using propensity-matching methodology, and significant heterogeneity was present between studies. In our analysis, which is the largest meta-analysis to
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date and was restricted to RCTs of DES in complex lesions, IVUS-guided PCI was associated
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with reduced rates of MACE by 35%, principally mediated by 38% and 37% reductions in TLR and TVR respectively. In contrast, while the rates of stent thrombosis and cardiovascular death
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were numerically lower in the IVUS-guided compared to the angiography-guided groups, these
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differences were not statistically significant, and rates of MI were comparable with the two approaches. While these data strongly support the role of IVUS-guidance to improve the efficacy of DES implantation, further studies are warranted to determine whether IVUS enhances the safety (MI, stent thrombosis and death) of PCI in the contemporary DES era. The benefits of IVUS in reducing the need for subsequent revascularization likely accrue from its ability to facilitate improved stent expansion and to minimize geographic miss and undetected edge dissections, collectively the greatest correlates of restenosis after bare metal stent and DES implantation (8). IVUS provides precise plaque, vessel and lumen measurements aiding in appropriate stent sizing. A smaller stent area has consistently been shown to be the
ACCEPTED MANUSCRIPT strongest predictor of both restenosis and early and late stent thrombosis (30,31). In this regard the minimum lumen diameter was numerically larger with IVUS-guided compared to
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angiography-guided PCI in 7 of 8 trials (15-17,25,26,28,29), and the % diameter stenosis was
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numerically lower in all 6 trials in which this data was reported (15-17,25,26,29), consistent with enhanced stent optimization. In addition, IVUS-guided PCI helps in detection of stent-related
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complications such as incomplete stent apposition, incomplete lesion coverage, edge dissections,
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stent fracture, tissue protrusion, and residual thrombus, findings that are often inapparent by angiography.
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It should be emphasized that all the trials in the present meta-analysis were performed in patients with complex lesion or patient characteristics. PCI of complex lesions has been
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associated with worse short-term and long-term outcomes (32). In such interventions, IVUS-
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guided PCI may guide not only the stent deployment but also the selection of treatment approaches according to lesion morphology, such as direct stenting, plaque modification with
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rotational atherectomy, etc. which may improve early and late outcomes. However, it is
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uncertain if similar benefit with IVUS-guidance will be observed in low-risk patients or lesions in whom the long-term prognosis is excellent with contemporary DES. Currently, the American College of Cardiology Foundation/ American Heart Associate PCI guidelines (33) recommend IVUS as a potential diagnostic tool for the assessment of angiographically indeterminate left main stenosis (class IIa, level of evidence B), cardiac allograft vasculopathy (IIa, B), evaluation of the mechanism of in-stent restenosis (IIa, C), assessment of intermediate non–left main coronary stenoses (IIb, B), and for guidance of coronary stent implantation, particularly in cases of left main stenting (IIb, B). The lack of any class I guideline recommendations for IVUS-
ACCEPTED MANUSCRIPT guidance emphasizes the need for additional adequately powered RCTs to evaluate the role of routine IVUS-guided PCI in patients with different risk profiles and lesion morphologies.
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Limitations. The present study has several limitations. First, all the trials enrolled
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patients undergoing complex coronary interventions, limiting the generalizability of the results. Second, in absence of patient-level data, we were unable to adjust our analysis for severity of
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presentation, lesion characteristics, use of various anticoagulants and anti-platelet therapy, or
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different stent types. However, the meta-regression analysis suggested that IVUS-guidance is of greatest benefit in particularly high-risk patients and lesions (acute coronary syndromes, diabetes
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and long lesions). Additional studies are required to determine the utlilty of IVUS-guidance for DES implantation in non-complex lesions. Third, two trials included in our analysis (26,28) were
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single-center studies which may introduce some degree of institutional or operator bias (although
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no statistical heterogeneity was observed between studies for any of the endpoints). Fourth, the IVUS criteria for stent optimization after PCI varied among trials, (Supplement Table 6) as did
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the specific definitions for MACE and MI. As such the results of the present study should be
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considered hypothesis-generating. Fifth, all of the trials examining outcomes of IVUS guidance in the DES era have exclusively enrolled high-risk patients and/or lesions. No such trials were broadly inclusive. As a result, whether IVUS guidance of DES implantation in simpler lesions would yield similar results as those found in the present meta-analysis is unknown. Finally, although the present study is the most comprehensive meta-analysis of IVUS-guided vs. angiography-guided PCI with DES to date, we still lack adequate power to determine whether the trends toward reduced stent thrombosis and cardiovascular death are real, again emphasizing the need for future large-scale trials. Such studies should also include a cost-effectiveness component to determine the value of IVUS-guided intervention.
ACCEPTED MANUSCRIPT Conclusions. The present meta-analysis of 8 RCTs and 3,276 patients demonstrated a significant reduction in MACE, TVR and TLR with IVUS-guided compared to angiography-
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guided DES implantation in patients with complex lesions and clinical characterisitics. IVUS use
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to optimize acute stent outcomes should thus strongly be considered when performing PCI in such patients. Additional adequately powered trials would be useful to further define the role of
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IVUS-guided PCI in patients with different risk profiles and lesion morphologies, and to
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determine the optimal IVUS parameters and guidance strategies to maximize event-free survival
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after DES in complex case scenarios.
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Figure Legends Figure 1. Flowchart for study selection. A systematic search identified randomized trials in which high-risk paitents and/or complex lesions were allocated to DES implnatation with IVUS-
ACCEPTED MANUSCRIPT guidance vs. angiography-guidance. Non-randomized trials were excluded fom this metaanalysis, as were trials in which most of all patients were treated with bare metal stents. The
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stratified by stent type (personal communciation, Pedro Lemos).
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MOZART trial(34) was excluded as DES were used in <10 patients, and randomization was not
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Figure 2. Forest plot of pooled relative risks (95% confidence intervals) for (A) MACE, (B) all-cause death, and (C) cardiovascular death, for IVUS-guided compared to angiography-
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guided PCI with DES. Squares represent the risk ratio of the individual studies; Horizontal
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lines represent the 95% confidence intervals (CI) of the risk ratio. The size of the squares reflects the weight that the corresponding study contributes in the meta-analysis. The diamonds
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represents the pooled risk ratio or the overall effect.
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Figure 3. Forest plot of pooled relative risks (95% confidence intervals) for (A) myocardial
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infarction, (B) target vessel revascularization, (C) target lesion revascularization, and (D) stent thrombosis, for IVUS-guided PCI compared to angiography-guided PCI with DES.
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Other notations as in Figure 2.
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ACCEPTED MANUSCRIPT Table 1. Charateristics of the included trials AVIO 2013
CTO-IVUS 2015
HOME DES IVUS 2010
IVUS-XPL 2015
RESET 2013
Tan et al. 2015
Zhang et al. 2016
Center
Multicenter
Multicenter
Multicenter
Single-center
Multicenter
Multicenter
Single-center
Single-center
Inclusion criteria
CTO
Long lesions (≥28 mm), CTO, bifurcation lesions, small vessels (≤2.5mm), patients requiring ≥4 stents.
CTO
AHA lesion type B2/C, proximal LAD, left main disease, RVD <2.5 mm, lesion length >20 mm, instent restenosis, insulin dependent diabetes mellitus and ACS
Long coronary lesions requiring stent length ≥28 mm with RVD 2.5-4 mm
De novo lesion requiring a stent ≥28 mm in length in a vessel with a distal RVD ≥2.5 mm
Unprotected left main coronary artery stenosis
De novo lesion in a small vessel (diameter 2.25-2.75 mm)
Sample size
230
284
402
210
1400
543
123
84
DES+
DES
ZES/BES
SES, PES
EES
ZES, EES
SES
DES
Clinical FU
24 months
24 months
12 months
18 months
12 months
12 months
24 months
12 months
Primary endpoint
In-stent late lumen loss
Post-procedural in-lumen MLD
Cardiac death
MACE
MACE
MACE
MACE
Post-procedural in-lumen MLD
MACE
Death, MI, TLR, stent thrombosis
Cardiovascular death, MI or TVR
Cardiac death, MI, or TVR
Death, MI, TLR
Cardiac death, target lesion– related MI, or TLR
Cardiovascular death, MI,
Cardiac death, MI, or TLR
Cardiac death, MI, or TVR
NR
NR
Aspirin 300 mg for 1 month, then 100 mg lifelong, clopidogrel 75 mg for 12 months
NR
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Aspirin 100 mg, clopidogrel 75 mg for at least 12 months
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Dual antiplatelet regimen
Aspirin 100 mg lifelong, clopidogrel 75 mg for 6 months
Aspirin 100 mg lifelong, clopidogrel 75 mg for 12 months
stent thrombosis, or TVR
Aspirin 100 mg lifelong, clopidogrel 75 mg for 3-12 months*
* 3-month duration following E-ZES implantation versus 12-month duration following EES implantation, +predominatly first generation DES (76.1%). ACS: acute coronary syndrome, AHA: American heart association, CTO: chronic total occlusion, LAD: left anterior descending, DES: drug-eluting stents, BES: biolimus-eluting stent, PES: paclitaxel-eluting stent, SES: sirolimus-eluting stent, EES: everolimus-eluting stent, ZES: zotarolimus-eluting stent, MACE: major adverse cardiac events, MI: myocardial infarction, MLD: minimum lumen diameter, RVD: reference vessel diameter, TLR: target lesion revascularization, TVR: target vessel revascularization, NR: not reported.
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Stent type
PT CEP ED TE D MAMA NUNUS SCCRIP RI T PT
Year
AIR-CTO 2015
ACCEPTED MANUSCRIPT Table 2. Patient characteristics CTO IVUS
67/66
64/64
61/61
HOME DES IVUS 59/60
Male, %
89/80
82/77
81/81
73/71
Diabetes, %
30/27
24/27
35/34
42/45
Hypertension,
75/70
70/67
63/64
67/61
22/28
70/77
NR
39/39
35/31
35/34
21/30
NR
Age, mean
%
CABG, %
3/4
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Previous
77/76
63/60
32/30
34/30
NR
65/63
61/66
41/47
64/60
67/65
61/62
NR
48/60
40/35
22/26
22/17
44/47
52/52
8/8
37/32
5/4
1/3
16/21
NR
NR
15/16
17/14
11/10
NR
NR
NR
NR
2/3
14/10
3/2
NR
NR
NR
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NU 66/63
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PT
20/21
63/64
36/37
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Previous PCI,
64/64
50/60
smoker, %
%
Zhang et al.
62/69
%
Previous MI,
Tan et al.
66/55
%
Current
RESET
69/69
years
Dyslipidemia,
IVUSXPL
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AVIO
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AIRCTO
ACS, %
29/24
30/26
NR
72/60
49/49
47/49
70/66
NR
LVEF, %
55/56
55/56
NR
NR
63/62
NR
55/55
58/57
Data are presented as IVUS-guided / angiography-guided. ACS: acute coronary syndrome which includes acute MI and/or unstable angina, CABG: coronary atery bypass surgery, LVEF: left ventricular ejection fraction, MI: myocardial infarction, NR: not reported, PCI: percutaneous coronary intervention.
ACCEPTED MANUSCRIPT Table 3. Angiographic and procedural characteristics CTO IVUS
LAD, %
44/37
53/49
42/47
HOME DES IVUS 56/54
LCX, %
21/15
NR
14/16
11/15
RCA, %
35/46
NR
44/37
29/24
LM, %
0/3
NR
0/0
3/4
Multivessel disease, %
49/57
NR
39/31
Preprocedural RVD, mm
2.65±0.37/ 2.60±0.34
2.67±0.46/ 2.62±0.41
2.69±0.44/ 2.64±0.55
Lesion length, mm
29.0±17.4/ 30.6±18.7
27.4±15.9/ 25.5±15.0
MLD, mm
NR
0.76±0.46/ 0.65±0.45
Baseline stenosis, %
100/100
71.6±15.8/ 75.5±16.1
Stent number
1.6±0.9/ 1.5±0.8
IVUSXPL 65/60
RESET
T
AVIO
62/68
RI P
AIRCTO
Tan et al.
Zhang et al.
NR
48/52
15/13
NR
49/51
21/25
23/20
NR
56/44
0/0
0/0
100/100
0/0
31/33
41/38
66/63
NR
3.17±0.43/ 2.95±0.34
2.89±0.45/ 2.85±0.45
2.82/2.80*
NR
2.40±0.23/ 2.39±0.27
18.1±7.3/ 17.6±6.7
34.7±10.8/ 35.2±10.5
29.6/30.6*
NR
17.0±4.2/ 15.1±5.5
NR
1.1±0.4/ 0.97±0.36
0.83±0.42/ 0.82±0.43
0.95/0.93*
1.90±0.22/ 1.92±0.21
0.91±0.3/ 0.90±0.31
NR
82.3±7.6/ 79.2±9.3
71.1±14.3/ 71.4±14.4
NR
NR
77.8±9.1/ 77.8±8.5
NR
1.7±0.8/ 1.6±0.7
1.3/1.3
1.3±0.5/ 1.3±0.5
NR
NR
NR
3.05±0.46/ 2.86±0.37
2.95±0.38/ 2.86±0.36
2.91±0.52/ 2.85±0.41
NR
NR
NR
3.43±0.09/ 3.44±0.12
2.64±0.25/ 2.45±0.20
55±23/ 52±25
23.9±6.74/ 23.2±6.51
43.6±18.7/ 41.5±17.6
23.6/22.1
39.3±13.1/ 39.2±12.3
32.4/32.3*
21.5±6.4/ 18.2±4.9
26.1±4.5/ 23.3±5.8
Postprocedure MLD, mm
2.62±0.45/ 2.40±0.47
2.55±0.46/ 2.39±0.42
2.64±0.35/ 2.56±0.41
2.94±0.31/ 2.87±0.24
2.64±0.42/ 2.56±0.39
2.55/2.55*
3.44±0.12/ 3.43±0.09
2.77±0.19/ 2.53±0.21
Post procedure
10.9±5.7/ 13.8±10.1
13.9±7.3/ 15.5±7.9
9.0±9.8/ 10.2±10.9
14.6±7.1/ 15.3±6.1
12.8±8.7/ 13.7±8.1
NR
NR
6.7±2.6/ 7.9±2.5
Stent length, mm
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26.8±17.3/ 26.4±17.6
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Stent diameter, mm
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14/15
ACCEPTED MANUSCRIPT diameter stenosis, % Data are presented as IVUS-guided / angiography-guided. *Median values, LAD: left anterior descending artery, LCx: left
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circumflex artery, LM: left main, MLD: minimal lumen diameter, NR: not reported, RCA: right coronary artery, RVD: reference vessel diameter.