Coronary bifurcation lesions are defined by the European Bifurcation Club as coronary artery stenosis occurring adjacent to and/or involving the origin of large distal side branches, that is, the opening of the proximal main branch, distal main branch and peripheral branch (the opening and its 3–5 mm segment), and there are more than 50% vascular stenosis, accounting for 15% to 20% of coronary artery lesions in the percutaneous coronary intervention (PCI). It is a severe challenge in the PCI practice due to the overlapping of main and side branch vessels and the stenosis of side branch orifices can be aggravated by the implantation of main stents, which may lead to complete occlusion of side branch orifices.
Coronary angiography is the current golden standard for the diagnosis of coronary artery disease as a visual method but it has many limitations in its years of application. Computer-assisted quantitative coronary angiography overcomes the drawbacks of the visual method to a certain extent by providing a more accurate evaluation basis however quantitative coronary angiography indirectly determines the structure of the vascular wall by inferring the lumen which results in its major limitations compared to standard angiography techniques. Actually, atherosclerosis often occurs at the bifurcation of a coronary artery due to turbulence and low shear stress. Therefore, traditional coronary angiography with 2-dimensional imaging features can only judge the degree of atherosclerosis, not the accurate identification of its special morphological changes such as the real diameter of the lumen, plaque load, calcification, bifurcation angle, and plaque distribution. In this case, the apparence of intravascular ultrasound (IVUS) changes the position of patients.
In comparison, apart from the accurate evaluation on the distribution of plaques at the bifurcation and the nature of lesions, and the reasonable selection on interventional therapy strategies, IVUS could also realize the evaluation on the effect of stent implantation, the optimization on the interventional treatment of bifurcation lesions, the timely orientation on complications, and the improvements onthe clinical prognosis of patients. It has been reported that guided by IVUS can improve the clinical outcomes of patients with multiple overlapping drug-eluting stents. From 138 original citations, including 3 randomized trials and 12 observational studies with 24,849 patients, which reported that IVUS-guided drug-eluting stent implantation can optimize clinical outcomes. However, the use of IVUS during PCI in the treatment of coronary bifurcation lesions did not show significant clinical benefits in a large retrospective study, from which it could suggect that whether the IVUS can improve the clinical prognosis of patients still remains controversial.
By taking the outcome of patients as the observation point, this study infers the value of IVUS in complex bifurcation lesions through the specific clinical manifestations of patients, aiming to reduce the related clinical complications, the revascularization and hospitalization rate of patients while improving the success rate of interventional surgery.
2.1 Data source and search strategy
This accomplished meta-analysis of data resources was demonstrated and analyzed under the guidance of the conducting and reporting meta-analyses of observational studies (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Guided by search strategies such as Medical Subject Heading terms (MeSH) and keywords, PubMed, Embase, Web of Science, the Cochrane Library, as well as relevant major international conference, were searched for articles published from inception to 13th October, 2019, without restriction to the language. The following keywords such as coronary bifurcation lesions, IVUS, coronary angiography, and PCI were contained. Randomized controlled trials and observational studies comparing the IVUS with coronary angiography-guided PCI strategies were included in patients with coronary bifurcation lesions (true coronary bifurcation lesions, and other types of complex lesions). Due to the protocol of the review was not registered, no ethical approval or patient consent was required to cite those previous published studies, and the study has got support from ethics committee.
To improve the efficiency in the whole process, some criteria were also clearly confirmed. The appropriate criteria for the systems assessment in this meta-analysis included
- (1) the type of lesion as coronary bifurcation,
- (2) inclusion of clinical control objectsonly to IVUS versus coronary angiography,
- (3) available complete clinical outcomes, such as cardiac death, myocardial infarction, target lesion or vessel revascularization, stent thrombosis, cardiac death, major adverse cardiac events (MACE), and
- (4) more than or equal to 1 year follow - up time.
The excluded criteria in this meta-analysis included
- (1) studies with incomplete clinical end-point events correlating the above outcomes,
- (2) repetitive published studies,
- (3) studies without the availability of full-text articles, and
- (4) correlative studies that were not retrieved by the initial searching.
2.2 Outcome definition
The outcomes of this analysis were divided into early and late clinical endpoints according to follow-up duration. The early endpoint events limited to trials with in a follow-up duration of 1 year. The late endpoint events consisted of the early endpoint events limited to trials with a follow-up duration of more than 1 year. Coronary bifurcation lesions were classified according to the Medina classification, and true bifurcation was defined as both main vessel and side branch with more than 50% diameter stenosis [Medina classification (1,1,1,), (1,0,1) or (0,1,1)]. The death was considered as cardiac death unless non-cardiac reasons were indicated. The myocardial infarction was defined as elevation of cardiac enzymes (data for cardiac enzymes > 1 time of the upper normal limit (UNL) in the Chen et al  and ≥ 3 times the UNL in the remaining studies ), with or without new pathological Q waves. The cardiac enzymes, assessed for this aim, varied among the studies, including creatine kinase-myocardial band isoenzyme or troponin T or I. Clinically driven the target vessel/lesion revascularization (target vessel revascularization [TVR] or target lesion revascularization) was defined as any revascularization produce stenting or coronary artery bypass grafting performed. The MACE was defined as the composite endpoint of death, myocardial infarction, and TVR or stroke, and the 1 year end points included MACE and its components (including cardiac death, TVR/target lesion revascularization, stent thrombosis). The stent thrombosis was defined according to the academic research consortium definition.
2.3 Data collection and quality assessment
Four evaluators (Yang R.R., Lv Y.H., Guo C., and Li M.)searched for useful documents and removed the non-conforming documents after a clear reading and analysis on the title and abstract, respectively. The first author, year of publication, follow-up duration, page number, baseline characteristics, as well as clinical outcomes of the patients were involved. Moreover, the literature was also carefully re - screened according to inclusion and exclusion criteria. Any disagreement or uncertainty was resolved by a group consensus or by a third party (Wang Z.L.) if necessary. The quality evaluation of eligible studies and the observational studies were assessed by the Cochrane Collaboration's tool for randomized control trials  and the Newcastle - Ottawa scale checklist, respectively.
2.4 Statistical analysis
Data were analyzed by the statistical software Review Manager Version 5.3. (The Nordic Cochrane Centre, The Cochrane Collaboration Network, Copenhagen, 2014). Mantel–Haenszel odds ratio (OR) was used as effect analysis statistics, and the corresponding 95% of confident intervals (CI) were generated to represent the data. As to the heterogeneity among the results, the Higgins I2-test (the test level was set I2 > 50% was significant) was estimated. In this case, a random-effects model was used for meta-analysis. Therefore, to ensure the accuracy, the clinical heterogeneity was treated by subgroup analysis, sensitivity analysis, or only descriptive analysis, among which the sensitivity analysis was carried out by excluding 1 by 1. If the results showed that the combined OR value and 95% CI had no directional changes,it indicated that the mean was basically stable. Meanwhile, publication bias was assessed using funnel plots, and the statistical significance was accepted for a 2-sided P < .05.
3.1 Search results
A total of 379 relevant literature covering IVUS-guided PCI versus angiography-guided PCI strategies were retrieved in the initial examination. After eliminated ineligible documents by reading the title and abstract of each article, 5 studies met the predefined inclusion criteria in qualitative analysis and meta-analysis (Fig. 1).[10,11,16–18] The quality of the 5 studies is evaluated by Newcastl Ottawa Scale (Fig. 1).
3.2 Clinical characteristics
The clinical characteristics of the included studies are listed in Table 1. A total of 7830 patients were enrolled into this meta-analysis from 5 observational studies. Among them, there were 1631 and 6394 patients with coronary bifurcation lesions in the IVUS-guided PCI strategy and the coronary angiography-guided PCI strategy, respectively, with anaverage age range from 51 to 77 years. Among those patients, male patients accounted for 77.1% of all subjects. The majority of patients had high-risk factors for cardiovascular disease such as diabetes (27.6%), hypertension (67.0%), and hyperlipidemia (44.9%), respectively.
3.3 lesions and procedural characteristics
The lesions and procedural characteristics are summarized in Table 2. Among 8025 coronary bifurcation lesions, 20.0% of patients had a history of PCI and 6.5% of patients had a history of coronary artery bypass grafting. In addition, for patients with coronary bifurcation lesions, the proportion of anterior descending artery, left circumflex artery, and right coronary artery was 64.5%, 19.0%, and 6.8%, respectively. Among them, 82.8%, 4.8%, and 17.4% of patients with coronary bifurcation lesions after the Medina classification belonged to 1,1,1, 1,0,1, and 0,1,1, respectively. Meanwhile, the IVUS-guided PCI strategy was associated with a longer length (29.90 ± 11.20 vs 27.80 ± 10.70 mm), larger diameter (3.82 ± 0.33 vs 3.15 ± 0.31 mm) compared with the angiography-guided PCI.
3.4 Comparison of the early clinical endpoints between the IVUS-guided and angiography-guided PCI strategies
The MACE (OR = 0.55, 95% CI 0.42 - 0.70, P
< .0001) are statistically significant compared with the IVUS - guided and angiography-guided PCI strategies, except for cardiac death (OR = 0.68, 95% CI0.34 - 1.35, P = .27), target lesion or vessel revascularization (OR = 0.78, 95% CI 0.59 - 1.05, P
= .10), stent thrombosis (OR = 0.36, 95% CI 0.12 - 1.04, P = .06) (Fig. 2).
3.5 Comparison of the late clinical endpoints between the IVUS-guided and angiography-guided PCI strategies
The cardiac death in IVUS-guided PCI strategy are superior to those with angiography-guided PCI strategy (OR = 0.36, 95% CI 0.23 - 0.57, P < .00001) (Fig. 3)
3.6 Statistical heterogeneity and sensitivity analysis
The extreme heterogeneity in the MACE endpoint at the early MACE follow - up sensitivity analysis results showed that a single study was removed 1 by 1, which is basically in line with the research of Chen et al (2013) (Fig. 4). The publication bias test was not evaluated on account of the number of studies was less than 10 in this meta-analysis.
This meta-analysis aimed to determine the role of IVUS-guided PCI strategy in patients with coronary bifurcation lesions. The results show that the IVUS-guided revascularization could reduce the incidence of MACE in early follow-up and cardiac death in late follow-up, comparing with angiography-guided revascularization strategy.
The 2018 ESC/EACTS Guidelines on myocardial revascularization recommend the IVUS-guided revascularization (class II; level of evidence B) for patients with coronary bifurcation lesions based on previous clinical data.[19,20] It also suggested better clinical outcomes with IVUS-guided vs. angiography-guided PCI.[21,3] However, a study showed that the possibility of IVUS-guided revascularization was controversial after the emergence of some new Invasive imaging tools. Although the IVUS-guided revascularization was similar to Optical Coherence Tomography (OCT)-guided revascularization, the study showed that OCT-guided stent implantation is relatively more secure compared with IVUS-guided revascularization. Because IVUS-guided and OCT - guided have respective advantages, it could not decide which kind of intracavitary techniqueis more efficient. With the emergence of the IVUS-guided revascularization strategy, the improvement of clinical outcomes compared with those in whom the angiography-guided group was identified in this study. It could be used asa guideline recommendation for patients with coronary bifurcation lesions in clinical practice.
Previously studies showed that there was a significant difference in MACE between the IVUS - guided and angiography-guided revascularization strategies. In addition, there were consistent with the impact of complex bifurcation lesions on clinical outcomes after PCI drug-eluting stents. This meta-analysis also found that the lower risk of myocardial infarction (2.7% vs 15.5%) and target lesion revascularization or TVR event (1.9% vs 3.7%) benefited from the IVUS - guided strategy. It further proved that the lower MACE originated from lower risk of myocardial infarction and target lesion or vessel revascularization in the IVUS-guided strategy. However, the clinical outcome existed heterogeneous, the main reasons are similar toa study by Chen et al (2013), which showed that 2-stent technology may be the cause of inconsistency.
Additionally, this study also demonstrated that the risk of cardiac death reaching a statistical difference was limited to trials at different follow-up time. However, there was no significant difference in cardiac death between both different strategies when the follow - up duration was less than 1 year. This difference in cardiac death may be related to the discrepancies in baseline characteristics in the study by Chen et al (2013), such as the lesion site in the left anterior descending artery was 68.1% and 80.1% of Medina stratification belonged to 1,1,1. The meta-analysis showed that there was significant clinical benefits in MACE and late cardiac death. These results may be explained by the higher success rate of final kissing balloon inflation (13.4% vs 12.5%) at the operation process.
Nevertheless, these results should be explained and analyzed from different perspectives. First, an operation strategy mainly depended on dynamic factors such as the experience of the operator and the characteristics of patients. Second, reasons for different underlying pathologic processes might be that rigorous post-dilation after stent implantation guided with IVUS could be beneficial for a larger-size left main disease with stable plaque. However, it could be harmful in acute myocardial infraction with thrombus. Third, discontinuation of anti-platelet therapy also was a predictor of post-procedural stent thrombosis, although no specific anti-platelet therapy data about each study were obtained in this study. Fourth, different sample sizes and follow-up durations could be another factor. Although the exact mechanism of clinical benefits using IVUS at bifurcation lesions is not clearly explained, the complexity of coronary bifurcation lesions could be an adequate lesion subset for the investigation of the benefits of IVUS during PCI. The morphology and type of bifurcation are crucial factors for selecting optimal treatment strategies to approach bifurcation lesions. The IVUS - guidance may help define its geometry, plaque distribution including characteristics, and degree of side branch - ostium involvement before the procedure. In the true bifurcation, the complex anatomical/morphological features lesions masked with angiogram could be detected by IVUS.
Although this study included a non-randomized, retrospective and observational study, and rigorous statistical adjustments were presented with propensity score matching, confounding factors may still affect the results of the study. Patients at different baseline levels and stent types may have an undetermined effect on the outcome of clinical endpoint events. For example, whether IVUS was used or not by the operator during PCI, the operator was more inclined to patients with more stable hemodynamics and the best surgical strategy. However, the predefined criteria to optimize stent placement procedures were not used in this study. Although astonishingly significant differences between IVUS - guided and angiographic-guided PCI groups were carefully analyzed, other unknown reasons that may result in differences in clinical outcomes between the 2 groups are not comprehensively considered and analyzed. There all - time IVUS analysis is done using online software during PCI, which may be a source of error compared with standard commercial IVUS software. Finally, the sample size is insufficient to assess the low incidence of late stent thrombosis. Most importantly, the main drawback of this meta-analysis is that it only includes 1 recent study, resulting in relatively weak timeliness. In addition, IVUS - guided revascularization had no significant effect on early cardiac death. These limitations above may result in no significant reduction in early cardiac death.
The IVUS-guided PCI strategy was associated with more clinical benefits compared with angiography - guided PCI strategy in patients with coronary bifurcation lesions. These findings suggest that the IVUS - guided PCI strategy can be recommended as an optimization in this kind of patients.
Conceptualization: Zhi - Lu Wang, Yong - Hui Lv, Rong - Rong Yang.
Data curation: Rong - Rong Yang,Zhi - Lu Wang.
Funding acquisition: Zhi - Lu Wang.
Investigation: Zhi - Lu Wang.
Methodology: Chen Guo, Yong - Hui Lv, Min Lin, Ming - Bo Zhang.
Project administration: Rong - Rong Yang, Zhi - Lu Wang.
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