Outcomes of Chronic Total Occlusions in Coronary Arteries According to Three Therapeutic Strategies: A Meta-analysis with 6985 Patients from 8 Published Observational Studies

Objective To perform a systematic review and meta-analysis of studies comparing coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and medical treatment (MT) in patients with chronic total occlusions (CTOs). Methods We identified eligible observational studies published in the China National Knowledge Infrastructure database, PubMed, Excerpta Medica database, Google Scholar, Cochrane Library, Web of Science, and "Clinical trials" registration from 1999 to October 2018. Main outcome measures were all-cause mortality, cardiac death, major adverse cardiac events (MACEs), and myocardial infarction (MI). Results There were eight observational studies including 6985 patients. Patients' mean age was 64.4 years. Mean follow-up time was 4.3 years. Comparing with MT (2958 patients), PCI (3157 patients) presented decreased all-cause mortality (odd ratio [OR]: 0.46, 95% confidence interval [CI]: 0.36-0.60; P<0.001), cardiac death (OR: 0.40, 95% CI: 0.31-0.52; P<0.001), MACE (OR: 0.55, 95% CI: 0.43-0.71; P<0.001), and MI (OR: 0.40, 95% CI: 0.26-0.62; P<0.001). Comparing with MT, CABG (613 patients) presented lower all-cause mortality (OR: 0.50, 95% CI: 0.36-0.69; P<0.001) and MACE (OR: 0.50, 95% CI: 0.26-0.96; P=0.04), but not lower MI (OR: 0.23, 95% CI: 0.03-1.54; P=0.13) and cardiac death (OR: 0.83, 95% CI: 0.51-1.35). Comparing with CABG, PCI did not present decreased risk for those outcomes. Conclusions PCI or CABG was associated with better clinical outcome in patients with CTO than MT. PCI is not better than CABG in decreasing mortality, MI, cardiac death, and MACE in coronary CTO patients.


INTRODUCTION
Chronic total occlusion (CTO) has been reported to be in approximately 30% of patients with coronary heart disease [1,2] . Currently, the management of CTO remains a challenge. Three strategies of management of CTO, including coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and medical treatment (MT), have been usually utilized, but which strategy is the best choice remains controversial. Ladwiniec et al. [1] reported that PCI is associated with improved longterm survival compared with MT alone. Tomasello et al. [2] also because of irrelevant content, non-English and non-Chinese articles, animal subjects, outcomes of interest not reported, or other reasons. The remaining 25 studies were full-text reviewed, and five studies were excluded due to the fact of being case reports or reviews. Furthermore, 12 studies were excluded due to the absence of the interest outcomes reported. Finally, 10 studies [1][2][3][4][7][8][9][10][11][12] met the inclusion criteria, and two studies were further excluded due to duplicated data [12] and no exact data to be used [7] .

Data Extraction
Data were extracted by two investigators (X.X and Y.Y.Z), using standardized data extraction forms. Discrepancies were resolved by consensus. The following contents were collected: name of the first author, year of publication, ethnicity or geographic location of the study subjects, study design, procedural, management strategy, ages, gender, and relevant outcomes.

Outcomes
The primary outcomes for this systematic review were allcause mortality and MACE. Secondary outcomes were MI and cardiac death.

Methodological Quality
We performed this meta-analysis including study selection, data collection, and analysis, and reporting of the results according to the recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE) Group [13] .
We calculated weighted odds ratios (ORs) and 95% confidence intervals (CIs) for categorical variables. Heterogeneity test was performed using Cochrane Q-statistic and I 2 -statistic [14] . Pooled effect sizes were determined using a fixed-effects model (the Mantel-Haenszel method) when heterogeneity was negligible (I 2 < 50%) or a random-effects model (the DerSimonian and Kacker method) when significant heterogeneity was present (I 2 ≥ 50%). We also performed a sensitivity analysis to evaluate the effect of each study on the combined ORs by omitting each study in turn. Publication bias was visually estimated by assessing funnel plots and the Begg's test. All analyses were performed using RevMan 5.3 software (Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen) as described previously [15,16] .

Studies' and Patients' Characteristics
The characteristics of the eight studies that met eligibility criteria are displayed in Table 1. Of these, one is a prospective cohort study, one is an observational study, and six are retrospective cohort studies. The present analysis includes 6985 patients, of whom 2958 received MT, 3157 received PCI, and 613 received CABG. The mean age of the study participants was 64.4 years. The mean follow-up time was 4.3 years. The overall internal validity was moderate and is illustrated in Table 2.

All-Cause Mortality
Of the 6985 patients included in this meta-analysis, 836 (12%) died during follow-up. Comparing with MT, PCI presented Zheng YY, et al. -Treatment of CTO reported that PCI significantly improves the survival occurrence in comparison with MT and/or CABG. However, Fujino et al. [3] found out that PCI does not reduce the risk of death or major adverse cardiac events (MACEs), when added to MT. Yang et al. [4] also suggested that PCI did not reduce cardiac death compared with MT in the treatment of CTO. These observational studies and retrospective cohort studies have yielded conflicting results and no large multicenter randomized clinical trial (RCT) has ever tested whether PCI or CABG is superior to MT.
A recent meta-analysis comparing successful vs. failed PCI for CTO suggested that successful PCI recanalization of a CTO was associated with improved long-term clinical outcome compared with a failed intervention [5] . However, all the participants involved in this meta-analysis have received a CTO-PCI attempt. It is unclear how would be the prognosis of the CTO patients without a CTO-PCI attempt and receiving different management strategy. Therefore, the purpose of this study was to determine if PCI/CABG is associated with improved clinical outcomes compared with the outcomes of MT alone by performing a systematic review and meta-analysis of published studies.
Main outcome measures were all-cause mortality, cardiac death, MACEs, and myocardial infarction (MI). In the present study, we limited the search criteria to include studies published in the Chinese or English language. Additionally, we also identified studies by searching Clinicaltrials.gov and by hand-searching references cited in relevant publications as described previously [6] .

Data Sources and Study Search Strategy
In the present study, we included observational studies and cohort studies which: 1) enrolled patients with coronary CTO who received treatments of PCI, MT, or CABG; 2) compared the outcomes among treatments of MT, PCI, and CABG; and 3) reported all-cause mortality, MI, cardiac death, and MACE rates.
We excluded: 1) studies assessing the role of different treatment strategies in quality of life; 2) studies comparing outcomes of successful PCI vs. failure PCI for CTO unless the outcomes of MT or CABG were also reported; 3) studies that only focused on only one treatment strategy; and 4) studies not involving humans.

Study Selection
As shown in Figure 1, our initial search yielded 727 citations. Of these, 702 (96.6%) were excluded by title and abstract search

Publication Bias Analysis
In the present study, we utilized funnel plots to evaluate the publication bias of all included studies. No publication bias was identified in this meta-analysis ( Figure 3).

Sensitivity Analysis
Sensitivity analysis was performed to examine the influence of each study on the pooled ORs by deleting each study one at a time. The pooled ORs showed no significant change (Figure 4), suggesting the results are stable.

DISCUSSION
The results of this systematic review and meta-analysis of comparison of clinical outcomes among PCI, CABG, and MT  (Figure 2A). Similarly, comparing with MT, CABG presented lower all-cause mortality (OR: 0.50, 95% CI: 0.36-0.69; P<0.001) ( Figure 2B). And we did not find a significant difference between PCI and CABG groups in mortality rates ( Figure 2C).   in patients with coronary CTO show that PCI presented a 54% reduction in all-cause mortality, a 45% reduction in MACE, a 60% reduction in MI, and a 60% reduction in cardiac death, compared with MT. Similarly, CABG presented a 50% reduction in all-cause mortality and a 50% reduction in MACE, compared with MT. However, compared with CABG, PCI does not have the advantage of decreasing mortality, MI, cardiac death, and MACE in coronary CTO patients. This is the first meta-analysis to compare the clinical outcomes of revascularization vs. MT alone in the treatment of coronary CTO patients.

MACE
The association between revascularization and low risk for subsequent cardiovascular events may be causal. Revascularization may improve the clinical outcomes of CTO patients by reducing or eliminating myocardial ischemia, which has been linked to worse prognosis [17] . At present, our meta-analysis suggested that both PCI and CABG improve the clinical outcomes in comparison with MT. The rates of all-cause mortality, cardiac death, MI, and MACE observed in the MT group were relatively higher than those of the revascularization group (PCI or CABG). Therefore, the findings of the present study have a practical application for cardiologists and surgeons alike. Given the strong clinical benefit in patients with CTO, PCI/CABG may be the optimal management strategies. The incidence of CTOs in the coronary artery disease (CAD) population is from 13% to 24% [1,[18][19] , however, CTO-PCI was performed in only 5-14% of patients with CTO [20,21] . There are several factors which impact the management of CTO patients. Jolicoeur et al. [22] reported that the number of diseased vessels, absence of previous MI, and angina are the strongest predictors of undergoing CTO-PCI. However, following the development of modern techniques and devices for CTO recanalization, the indications are currently increasing. Our meta-analysis' results suggest that PCI/CABG are the best treatment strategies for CTO patients. Furthermore, although our results did not show significant differences in prognosis between CABG and PCI, comparing with MT, PCI presented decreased risks of mortality, cardiac death, MI, and MACE, but CABG only presented decreased risks of mortality and MACE, but not of MI and cardiac death. This fact suggested that PCI rather than CABG might be the best choice for CTO management strategy. However, the revascularization strategy may be influenced by the SYNTAX score and chronic total occlusion SYNTAX score (CTO-SS). In our meta-analysis we did not consider the effect of SYNTAX score and CTO-SS on management strategy selection because they were not provided in the original literatures. Therefore, our results should be further confirmed by future large-scale clinical studies.

Study Limitations
First, in our meta-analysis, many of the included studies had different entry criteria, study populations, clinical outcomes, and follow-up time. This is a source of increased heterogeneity that may limit the generalizability of our conclusions to the broader  coronary CTO population. Second, all the included studies are not randomized trials, therefore, the selection of the treatment group was likely influenced by patients' characteristics and patients' and doctors' preferences. Third, regarding the participants in each study, including both single CTO and multivessel CTO, we did not perform a subgroup analysis according to the number of CTOs, due to the absence of original data. Fourth, the comparison of PCI vs. CABG should be interpreted with caution, because the SYNTAX score and CTO-SS were not described in some included studies. Finally, optimization or standardization of MT will affect the clinical outcomes, which should not be underestimated. In our meta-analysis, a stratified analysis of MT was not performed due to the absence of related data in the included studies.

CONCLUSION
In this first systematic review and meta-analysis of PCI, CABG, and MT in patients with coronary CTO, PCI/CABG were associated with better prognosis than MT. However, PCI is not better than CABG in decreasing mortality, MI, cardiac death, and MACE in coronary CTO patients.