Comparison of Immediate Versus Staged Complete Revascularisation in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease: A Meta-Analysis of Randomized and Non-randomized Studies

Acute myocardial infarction is a critical medical condition that poses a significant health burden, leading to substantial morbidity. Despite advancements in medical care, managing this condition is challenging for patients and society. The preferred approach appears to be comprehensive multivessel revascularization, yet the optimal timing remains uncertain. This study aims to compare immediate complete revascularisation and stage complete vascularization in patients presenting with acute coronary syndrome (ACS) and multivessel coronary artery disease (MVD). The Preferred Reporting of Systematic Reviews and Meta-analysis (PRISMA) guidelines conducted the present meta-analysis. A comprehensive literature search was conducted using online databases, including PubMed, and EMBASE from 2010 onwards, to identify articles that compared cardiovascular outcomes between patients undergoing immediate and staged complete revascularization. We also searched Google Scholar for additional studies relevant to the present meta-analysis. The primary outcome assessed in this study was major adverse cardiovascular events (MACE). Secondary outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and revascularization. A total of 15 studies fulfilled pre-defined eligibility criteria and were included in the final analysis. Our analysis shows that staged revascularization is associated with improved outcomes in patients with ACS and multivessel CAD, including all-cause mortality and cardiovascular mortality, without increasing the risk of major adverse cardiovascular events, myocardial infarction, and the need for unplanned revascularization.


Introduction And Background
Acute myocardial infarction is a critical medical condition that poses a significant health burden, leading to substantial morbidity.Despite advancements in medical care [1], managing this condition is challenging for patients and society.Percutaneous coronary intervention (PCI) is fundamental in treating Acute Myocardial Infarction (AMI) patients.Notably, over 50% of AMI patients likely have multivessel coronary artery disease (MVD), often linked to unfavorable outcomes [2][3].Patients with MVD tend to have a less favorable prognosis than those with only one affected vessel [4].The guidance in ST-elevation myocardial infarction (STEMI) protocols was established based on multiple randomized controlled trials (RCTs) that showed that complete revascularization yields better results than a strategy focusing solely on the culprit lesion, particularly regarding major adverse cardiovascular events (MACE).However, this positive effect was primarily driven by the reduced need for revascularization and the reduction in angina [5][6].The recent COMPLETE trial, for the first time, demonstrated that complete revascularization has an advantage over the primary endpoint of myocardial infarction (MI) or cardiovascular mortality [7].
The preferred approach appears to be comprehensive multivessel revascularization, yet the optimal timing remains uncertain.This procedure can be conducted either during the index procedure or intervention or in a staged manner.In the latter case, staged revascularization can be performed either during the same hospitalization or even on an outpatient basis.Due to limited data, the STEMI guidelines do not provide specific recommendations regarding the timing of revascularization.According to the SMILE study, the NSTE-ACS guidelines mention that considering complete revascularization during the initial procedure may be contemplated (Class IIB, LOE B) [8][9].Dangas  in patients with MVD, relying on the insights of interventional cardiology specialists.Their findings revealed that around 80% of surveyed interventional cardiologists propose delayed staged PCI for STEMI patients, while 37% advocate a similar approach for patients with non-STEMI (NSTEMI).Regarding the timing of staged PCI, 62% of cardiologists suggested a waiting period of more than two weeks for STEMI patients, and 55% recommended a similar timeframe for NSTEMI patients.The variability in decisionmaking stems from numerous factors that impact the timing and choice of staged revascularization [10].
This systematic review and meta-analysis aimed to compare immediate complete revascularization during the index procedure versus staged complete revascularisation in patients presenting with ACS (including STEMI and NSTE-ACS) and MVD.Because of the limited data, this systematic review included RCTs and non-randomized trials.

Review Methodology
The present meta-analysis was conducted in accordance with the Preferred Reporting of Systematic Review and Meta-analysis (PRISMA) guidelines.

Literature Search
A comprehensive literature search was conducted using online databases, including PubMed, and EMBASE, from 2010 onwards to identify articles that compared cardiovascular outcomes between patients undergoing immediate and staged complete revascularization.We also searched Google Scholar to find additional studies relevant to the objective of this study.Key terms used to search for relevant articles included "immediate revascularization," "staged revascularization," "acute coronary syndrome," and "multivessel disease."We used synonyms, Medical Subject Heading (MeSH) terms to further sensitize the search to identify additional articles; the reference lists of included articles were also manually searched.The literature search was performed independently by two authors.

Study Selection with Inclusion/Exclusion Criteria
Two authors independently screened articles to identify eligible studies.Discrepancies were resolved through consensus and discussion.Studies were considered eligible for inclusion in this meta-analysis if they met the pre-defined criteria: (a) any randomized controlled trial (RCT) or observational study comparing cardiovascular outcomes between immediate and staged complete revascularization in patients with ACS (STEMI or NSTEMI) and MVD, (b) published in the English language, and (c) reported the required outcomes.Studies with a follow-up duration of less than 12 months were excluded.Additionally, articles that included patients with cardiogenic shock were excluded.Case reports, editorials, meta-analyses, and systematic reviews were also excluded.

Data Extraction, Outcomes, and Risk of Bias Assessment
Data were extracted from the included studies using a standardized data collection form developed in Microsoft Excel (The Microsoft Corporation).The extracted data included author names, publication years, study designs, sample sizes, ages, genders, diabetes mellitus, hypertension, type of ACS, and dyslipidemia.The primary outcome assessed in this study was major adverse cardiovascular events (MACE).Secondary outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and revascularization.Two authors independently performed the risk of bias assessment for each included study.The Cochrane Risk of Bias Assessment tool was used for RCTs, and the Newcastle-Ottawa Scale (NOS) was used for observational studies.

Statistical Analysis
For the purpose of data analysis, we employed RevMan Version 5.4.1 (The Cochrane Collaboration, London, United Kingdom).We reported the risk ratio (RR) with a 95% confidence interval (CI) to compare the outcomes between the two study groups.A p-value of less than 0.05 was considered to indicate significance.Heterogeneity was assessed using I-square, and a threshold of I-square >50% was used to determine significant heterogeneity.In instances of notable heterogeneity, a random-effects model was applied to compare the outcomes.Otherwise, the analysis was conducted using a fixed-effect model.Subgroup analysis was performed based on study design (randomized and non-randomized studies).

Results
Online database searches led to 1066 studies.As 56 studies were duplicates, we removed them before the initial screening.Initial screening was done for the remaining articles using their titles and abstracts.Out of 1010 studies, 33 studies were eligible for full-text screening.Finally, 15 studies fulfilled pre-defined eligibility criteria and were included in the final analysis.Figure 1 shows the PRISMA flowchart demonstrating the study selection process.Table 1 shows the characteristics of included studies.Out of 15 studies, 5 were RCTs.Follow-up duration of included studies ranged from 12 months to 54 months.Figure 2 shows the risk of biased assessment of RCTs.The quality assessment of observational studies is shown in Table 2.

Major Adverse Cardiovascular Events (MACE)
The analysis of major adverse cardiovascular events (MACE) encompassed 10 studies.No significant difference was found between immediate and staged revascularization (RR: 1.02, 95% CI: 0.80-1.29),as shown in Figure 3. Significant heterogeneity was reported among the study results.

All-cause Mortality
The assessment of all-cause mortality involved a comprehensive review of 14 studies.As shown in Figure 4, the risk of all-cause mortality was 1.50 times higher in the immediate revascularization group compared to staged revascularization patients (RR: 1.50, 95%: 1.10 to 2.05).Significant heterogeneity was reported among the study results.
No significant heterogeneity was reported among the study results.

Myocardial Infarction and Revascularization
The pooled analysis focusing on myocardial infarction involved 11 studies.When comparing immediate revascularization with the staged approach, the calculated RR is 0.95, with a 95% CI ranging from 0.74 to 1.22, as shown in Figure 6.No significant difference was found between the two groups.Pooled analysis of 11 studies showed no significant difference between immediate and stage complete revascularization in terms of revascularization (RR: 0.84, 95% CI: 0.65 to 1.10), as shown in Figure 7.

Subgroup Analysis
The results reveal intriguing patterns in the analysis of outcomes across subgroups, as shown in Table 3.For major adverse cardiovascular events (MACE), within randomized controlled trials (RCTs), immediate revascularization demonstrates a lower risk in the immediate group (RR: 0.97, 95% CI: 0.64 to 1.46) despite a moderate degree of heterogeneity (I-square: 71%).In non-RCTs, the risk is slightly elevated in the immediate group (RR: 1.08, 95% CI: 0.79 to 4.46), but the differences overall non-significant All-cause mortality showcases a distinct contrast: RCTs exhibit significantly higher risk (RR:

Discussion
The current meta-analysis of 15 studies has found that in patients with ACS and multivessel CAD, staged revascularization is associated with improved outcomes, including all-cause mortality and cardiovascular mortality, without increasing the risk of major adverse cardiovascular events, myocardial infarction, and the need for unplanned revascularization.
Both meta-analyses and RCTs have consistently reported that complete revascularization is associated with improved outcomes in patients with ACS and multivessel CAD [26][27][28].However, the optimal timing of complete revascularization remains unclear, with most of the data coming from observational studies only.
A study conducted by Bainey and colleagues performed a meta-analysis showing that performing complete revascularization using MVI-S along with IRA PCI resulted in improved survival rates in both the short and long term while using MVI-I led to higher in-hospital mortality when compared to only IRA PCI [29].A more recent network meta-analysis by Tarantini et al. found that MVI-S was linked to decreased short-term and long-term mortality compared to both IRA-only PCI and MVI-I.However, using only IRA PCI was associated with lower mortality rates than MVI-I [30].Gaffar et al. conducted a meta-analysis exclusively focused on research contrasting prompt, complete revascularization with gradual complete revascularization within STEMI and NSTEMI patient groups.
Nevertheless, their selection criteria were limited to randomized controlled trials (RCTs), including only four RCTs encompassing a total of 853 patients.The immediate complete revascularization group exhibited notably reduced instances of unplanned repeat revascularization, alongside a suggestive inclination towards lower rates of major adverse cardiovascular events (MACE) [31].In contrast to previous meta-analyses, we included NSTE-ACS as well as STEMI.Moreover, we included only those RCTs and observational studies in which staged and immediate complete revascularization were performed.This approach helped create a more homogeneous study population, allowing a true head-to-head pooled analysis.Additionally, our metaanalysis included recently conducted RCTs.
The present meta-analysis supports the use of staged revascularization in terms of safety.The reasons why multivessel intervention during the index primary PCI procedure may not be safe are unknown but are likely multifactorial.Any PCI procedure is challenging in the setting of hemodynamic instability and left ventricular dysfunction.The prothrombotic and inflammatory milieu in the early phase of STEMI may also increase procedural risks [32][33].Second, lesion severity in non-culprit vessels can be overestimated during primary PCI because of diffuse coronary vasoconstriction and systemic endothelial dysfunction [34].Third, multivessel PCI increases contrast use, which may be less tolerated in STEMI patients, especially if radiocontrast nephropathy develops [35].Finally, unforeseen periprocedural complications in the nonculprit vessel may be poorly tolerated due to the "double jeopardy" of large myocardial territories at risk (i.e., simultaneous impairment of the culprit and non-culprit regions) [18].
The selection of an approach impacts treatment effectiveness and patient well-being and has implications for expenses and reimbursements.Implementing a staggered MV-PCI strategy leads to higher patient medical costs than an immediate MV-PCI approach [36][37].Most national insurance committees, including those in China, tend to discourage using staggered PCI methods.Thus, cardiologists need to balance the economic downsides of staged MV-PCI against potential positive effects on patient outcomes.Surprisingly, in the current study, nearly half of the MV-PCI recipients opted for the staged approach, contrasting with the 21.2%rate reported in the Korean study [38].There is an urgent requirement for compelling evidence to rationalize the additional expenses associated with staged MV-PCI.The present study highlights that a staged intervention could align with patients' best interests, providing a strong basis to advocate for staged interventions in cases of ACS and MVD.However, it is important to note that this study was observational and inherently limited; comprehensive, well-powered trials comparing these two strategies are essential.
Our meta-analysis supports the current recommendations for revascularization of the non-infarct-related artery in patients with ACS and multivessel disease.The optimal strategy for managing STEMI alongside multivessel disease involves pursuing comprehensive revascularization.To capitalize on survival advantages, begin with primary percutaneous coronary intervention (PPCI) targeting the infarct-related artery (IRA).Subsequently, adopt a consistent staged revascularization approach for stable non-IRA lesions to mitigate potential future adverse clinical occurrences.This staged PCI should ideally take place either during the initial hospital stay or within 45 days after the initial procedure, adhering to local protocols and available resources [39].
Our analysis is subject to several limitations.Firstly, variations in the timing of staged revascularization (MVI-S) across different studies introduced heterogeneity, preventing the identification of optimal timing.Secondly, we were unable to ascertain if specific patient subgroups experienced greater advantages from MVI-I compared to MVI-S.Thirdly, the absence of access to individual patient data hindered the possibility of conducting analyses based on patient-specific attributes.Lastly, discrepancies in the definition of multivessel coronary artery disease (CAD) and the interpretations of outcome measures like major adverse cardiovascular events (MACE) and repeat revascularization contributed to heterogeneity.

Conclusions
In conclusion, this comprehensive meta-analysis provides valuable insights into the optimal timing for revascularization in patients with acute coronary syndrome (ACS) and multivessel coronary artery disease (CAD).The findings suggest that staged revascularization is associated with improved outcomes in all-cause mortality and cardiovascular mortality compared to immediate revascularization.No significant differences were observed in major adverse cardiovascular events or myocardial infarction between the two approaches.
In clinical practice, these findings suggest that a staged revascularization approach, following an initial primary percutaneous coronary intervention targeting the infarct-related artery, could lead to better outcomes in patients with ACS and multivessel CAD.However, the decision-making process should consider individual patient factors, available resources, and local protocols.

FIGURE 1
FIGURE 1: PRISMA flowchart of study selection