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Intravascular Ultrasound Imaging–Guided Versus Coronary Angiography–Guided Percutaneous Coronary Intervention: A Systematic Review and Meta‐Analysis

Background Intravascular ultrasound (IVUS) guidance during percutaneous coronary intervention (PCI) offers tomographic images of the coronary vessels, allowing optimization of stent implantation at the time of PCI. However, the long‐term beneficial effect of IVUS over PCI guided by coronary angiography (CA) alone remains under question. We sought to investigate the outcomes of IVUS‐guided compared with CA‐guided PCI. Methods and Results We performed a comprehensive search of PubMed, Medline, and Cochrane Central Register, looking for randomized controlled trials and observational studies that compared PCI outcomes of IVUS with CA. Data were aggregated for the primary outcome measure using the random‐effects model as pooled risk ratio (RR). The primary outcomes were the rate of cardiovascular death, need for target lesion revascularization, occurrence of myocardial infarction, and rate of stent thrombosis. A total of 19 studies met the inclusion criteria, comprising 27 610 patients divided into IVUS (n=11 513) and CA (n=16 097). Compared with standard CA‐guided PCI, we found that the risks of cardiovascular death (RR, 0.63; 95% CI, 0.54–0.73), myocardial infarction (RR, 0.71; 95% CI, 0.58–0.86), target lesion revascularization (RR, 0.81; 95% CI, 0.70–0.94), and stent thrombosis (RR, 0.57; 95% CI, 0.41–0.79) were all significantly lower using IVUS guidance. Conclusions Compared with standard CA‐guided PCI, the use of IVUS imaging guidance to optimize stent implantation is associated with a reduced risk of cardiovascular death and major adverse events, such as myocardial infarction, target lesion revascularization, and stent thrombosis.

P ercutaneous coronary intervention (PCI) is a mainstay for the treatment of coronary artery disease, a major cause of morbidity and mortality worldwide. 1 Although coronary angiography (CA) is the standard imaging modality used for coronary stent implantation, it is limited to 2-dimensional projections of coronary anatomical characteristics. This limitation can be overcome using high-resolution intracoronary imaging modalities, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), that offer detailed 3-dimensional tomographic views of coronary plaque, blood vessel, and stent morphological characteristics, thus enabling greater information to guide optimal stent implantation. [2][3][4][5] Several randomized controlled trials (RCTs) and observational studies examining intracoronary imaging during and after stent implantation have demonstrated that IVUS-guided stent implantation was associated with the reduction of major adverse cardiac events and target vessel revascularization in patients with complex coronary lesions, including long lesions, severe calcification, bifurcations, chronic total occlusions, and unprotected left main disease. [3][4][5][6][7] However, despite accumulating data supporting the use of IVUS to optimize PCI, the adoption of intracoronary imaging to guide stent implantation in real-world interventional clinical practice remains low, in part because of a perceived lack of supporting clinical evidence. 8 Therefore, we sought to synthesize all available data by conducting a comprehensive meta-analysis exploring the clinical outcomes of PCI guided by angiography with adjunctive IVUS imaging compared with angiography alone.

Inclusion Criteria
We searched Medline, EMBASE, and Cochrane library for RCTs or observational studies that compared IVUS with CA outcomes as invasive imaging modalities for guiding PCI with stent implantation. Studies using both bare metal stents and drug-eluting stents (DESs) were eligible. In an attempt to decrease the risk of bias inherent with including observational studies, only nonrandomized studies that used matching algorithms were included. We also excluded all the studies that used intravascular imaging for stent implantation in the presence of flow-limiting dissections or residual stenosis after plain balloon angioplasty. The analysis was restricted only to studies in which at least 100 patients were enrolled in each treatment arm. The data that support the findings of this study are available from the corresponding author upon reasonable request.
The combinations of medical terms "percutaneous coronary intervention,"" intravascular ultrasound," "intravascular imaging," "IVUS," and/or "coronary angiography" were used to conduct a comprehensive search in the above-mentioned databases. All searches were restricted to studies conducted in human subjects published from the date of the databases' inception through April 2019. There was no language restriction or use of additional filters. A cross-reference check of previously published reviews and/or meta-analyses on this topic was performed. The literature searches and all analyses were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for network meta-analyses 9 ( Figure 1).

End Point Outcomes
The primary outcome of this meta-analysis was cardiovascular mortality. Secondary end points were myocardial infarction (MI), target lesion revascularization (TLR), and stent thrombosis (ST).

Data Extraction and Statistical Analysis
After careful title checking and reviewing full texts of all the studies, 2 investigators (E.O. and M.A.) independently verified the inclusion criteria and abstracted the data from all the articles that met the inclusion criteria. Disagreements were resolved by consensus. All extracted data from the included studies were collected into a spreadsheet and verified by a third author (Y.A.). Summarized and weighted means and rates from each individual trial or observation study for baseline characteristics were reported. Data were pooled for the primary and secondary outcomes using summary risk ratios (RRs) and 95% CIs using random effects models, while taking into account the within and between study variance. Two-sided P values were calculated, with P<0.05 considered significant for all tests. Heterogeneity was assessed by means of the I 2 statistic (with an I 2 value >50% being considered the result of severe heterogeneity). Sensitivity analysis was performed for different study design and baseline characteristics to evaluate for the consistency of the main results across all studies that were included in the analysis. Sensitivity analysis and metaregression were used to explore the treatment effect and elucidate the relationship between confounding factors and IVUS guidance. We used a linear regression (Littenberg and Moses linear model) approach. 10 Random-effects model was selected because of the difference in the designs of the studies included in this meta-analysis (observation versus RCTs). A 2-tailed P<0.05 was considered statistically significant. All data and supporting materials have been provided with the published article, and all supporting data are available within the article.
The methodological quality of observational studies was assessed by the Newcastle-Ottawa scale, which consists of 3

Clinical Perspective
What Is New?
• This study demonstrated that use of intravascular ultrasound imaging-guided percutaneous coronary intervention was associated with lower cardiovascular death, myocardial infarction, target lesion revascularization, and stent thrombosis, compared with coronary angiography alone. • Our study encourages the routine use of intracoronary imaging to optimize coronary stent implantation.
What Are the Clinical Implications?
• Intracoronary imaging is an innovative technology presented to overcome the limitations of standard routine angiography. • This technique offers more details about the coronary atherosclerotic plaque, vessel wall, and facilitated stent delivery, which subsequently improve the outcomes of percutaneous coronary interventions. • The routine use of intracoronary imaging to optimize coronary stent implantation is encouraged.
factors: patient selection, comparability of the study groups, and assessment of outcomes. A score of 0 was considered as an exclusion criterion from a statistical standpoint, and we selected a score cutoff of 0.7 and 1 for observational studies and RCTs, respectively, to ensure the consistency of our meta-analysis results. 11,12 Results Nineteen eligible studies, including a total of 27 637 patients, were identified in the current meta-analysis, with 11 540 patients in the IVUS guidance group and 16 097 patients in the CA guidance group. The detailed study design included in this meta-analysis is summarized in Table 1. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Patient characteristics are summarized in Table 2. 29 Full-text articles excluded, with reasons (n = 16) -Review or Meta-analysis: 5 -Studies did not include cardiovascular death -Studies did not include ST, -Studies did not include MI and/or TVR -Studies not pertinent to IVUS -Studies not pertinent to CA -100 patients were enrolled in each treatment arm

Discussion
The principal findings from this study are as follows: metaanalysis of 19 studies showed that, compared with CA alone, IVUS-guided PCI (1) decreased the risk of cardiovascular death, with a relative risk reduction of 33%; (2) lowered MI risk, with a number needed to treat of 91 to prevent 1 MI; (3) decreased the need for TLR; and (4) was associated with less ST.
Since the inception of PCI decades ago, x-ray CA has been the standard imaging platform used to guide coronary intervention procedures. However, a major drawback of CA is that it relies on 2-dimensional projections to define the structure of complex 3-dimensional coronary artery lumens. In the modern era, through the use of IVUS and OCT,  intracoronary imaging can overcome the inherent limitations of CA by providing high-resolution axial cross-sectional images with detailed tomographic structural information on lesion and vessel characteristics. Thus, intracoronary imaging promotes an enhanced understanding of coronary anatomical characteristics at the time of PCI, facilitating protocols to optimize coronary stent sizing, avoid stent malapposition and underexpansion, and identify unrecognized complications, such as edge dissection. Overall, by precisely guiding stent implantation at the index procedure, intracoronary imaging aims to improve short-and long-term cardiovascular PCI outcomes.
In the bare metal stent era, a meta-analysis of 7 randomized trials showed a neutral effect on mortality and MI over a follow-up period of 6 months to 2.5 years; however, IVUS use was associated with a reduction in both angiographic restenosis at 6 months and the rate of subsequent revascularization. 32 These early encouraging results coupled with the introduction of DESs paved the way for IVUS-guided DESs as an attractive strategy to further improve PCI outcomes. Indeed, the evidence base supporting the theoretical benefits of an IVUS-guided DES implantation approach has been increasing over the past several years, with several meta-analyses and randomized studies showing a decrease in major adverse cardiac events, [33][34][35][36][37][38][39][40] particularly in complex lesions and high-risk patients.
The recently completed all-comers ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "AllComers" Coronary Lesions) trial, enrolling 1148 patients in the largest randomized IVUS-guided PCI trial to date, demonstrated that the routine use of IVUS during DES implantation reduced cardiovascular death and ST when compared with CA alone. These findings are reinforced by the current study, the largest IVUS-guided PCI meta-analysis performed pooling 19 observational studies and RCTs with a total of 29 637 patients with complex and noncomplex coronary lesions and long-term follow-up between 6 and 64 months. Although the variation in the included studies created low to moderate outcome heterogeneity, the overall I 2 remained <50%. To investigate the sources of moderated heterogeneity in our study, additional meta-regression analyses were performed to evaluate the relationship between study characteristics and IVUS use, revealing that IVUS guidance continued to demonstrate benefit over CA-guided PCI, irrespective of the presence of diabetes mellitus, acute coronary syndrome, hypertension, sex, or left main lesion location.
Overall, accumulating clinical studies support the use of intracoronary imaging to improve outcomes after stent implantation. However, despite increasingly compelling data, the use of intracoronary imaging guidance during PCI procedures continues to be significantly underused in the United States. A recent report showed that intracoronary imaging (IVUS and/or OCT) in the United States increased from 2.1% in 2004 to 6.6% in 2014, heavily weighted toward IVUS (94.3% IVUS versus 6.6% OCT). 41 The infrequent use of intracoronary imaging by many operators may be explained by perceived time or cost constraints or a belief that visual assessment of coronary anatomical characteristics with x-ray angiography is sufficient. 42,43 However, multiple studies have demonstrated that angiographic lesion assessment alone is severely limited, especially in complex lesions, 44 and that intracoronary imaging is cost-effective by preventing the need for repeated procedures. 45 Although the data supporting the benefit of intracoronary imaging-guided PCI on cardiovascular outcomes are limited to IVUS to date, a recent trial comparing IVUS with a protocolized OCT stent implan tation algorithm demonstrated similar short-term procedural results, 46 implying that OCT may offer similar long-term benefits to IVUS. The ongoing ILUMIEN IV (Optical Coherence Tomography [OCT] -Guided Coronary Stent Implantation Compared to Angiography) trial, which will enroll up to 3650 patients, focusing on high-risk, complex disease at 125 international centers, comparing outcomes after coronary stent implantation using OCT with routine CA will provide further important insight into the generalizability of an intracoronary imaging-guided PCI approach. 47 This study has several limitations. First, as specific IVUS criteria for optimal stent implantation were not precisely described or consistent among studies, preintervention imaging assessment and stent postdilation were often at the discretion of the operator, likely leading to variability in the final stent result. Second, studies included in the current analysis used both firstand second-generation DESs as well as bare metal stents, which could affect the outcome. Third, our analysis included a mixture of lesion locations and multivessel disease interventions. Fourth, the definition of cardiovascular death and ST (probable versus definite) varied substantially among included studies and played a role in creating heterogeneity. To mitigate this influence, we avoided unadjusted cohorts and down weighted/excluded observational studies in multiple sensitivity analyses. Finally, we did not have access to individual patient data, and therefore, our findings should be interpreted cautiously in view of the inability to perform specific types of analysis with study-level data.

Conclusions
IVUS imaging-guided PCI was associated with lower cardiovascular death, MI, TLR, and ST, compared with CA alone. These results encourage the routine use of intracoronary imaging to optimize coronary stent implantation.