Effect of early metoprolol before PCI in ST‐segment elevation myocardial infarction on infarct size and left ventricular ejection fraction. A systematic review and meta‐analysis of clinical trials

Abstract Aim This meta‐analysis aims to look at the impact of early intravenous Metoprolol in ST‐segment elevation myocardial infarction (STEMI) before percutaneous coronary intervention (PCI) on infarct size, as measured by cardio magnetic resonance (CMR) and left ventricular ejection fraction. Methods We searched the following databases: PubMed, Scopus, Cochrane library, and Web of Science. We included only randomized control trials that reported the use of early intravenous Metoprolol in STEMI before PCI on infarct size, as measured by CMR and left ventricular ejection fraction. RevMan software 5.4 was used for performing the analysis. Results Following a literature search, 340 publications were found. Finally, 18 studies were included for the systematic review, and 8 clinical trials were included in the meta‐analysis after the full‐text screening. At 6 months, the pooled effect revealed a statistically significant association between Metoprolol and increased left ventricular ejection fraction (LVEF) (%) compared to controls (mean difference [MD] = 3.57, [95% confidence interval [CI] = 2.22–4.92], p < .00001), as well as decreased infarcted myocardium(g) compared to controls (MD = −3.84, [95% [CI] = −5.75 to −1.93], p < .0001). At 1 week, the pooled effect revealed a statistically significant association between Metoprolol and increased LVEF (%) compared to controls (MD = 2.98, [95% CI = 1.26−4.69], p = .0007), as well as decreased infarcted myocardium(%) compared to controls (MD = −3.21, [95% CI = −5.24 to −1.18], p = .002). Conclusion A significant decrease in myocardial infarction and increase in LVEF (%) was linked to receiving Metoprolol at 1 week and 6‐month follow‐up.


| INTRODUCTION
ST-segment elevation myocardial infarction (STEMI) is the most important condition with a high mortality rate and hospitalization for coronary artery disease patients. It requires urgent and immediate intervention. 1 A new era of enhancement in the outcome of STEMI patients has emerged. 2 Although recurrent cardiovascular events such as congestive heart failure, arrhythmia, and sudden death are the significant probability incidence for STEMI survivors. 3,4 The standard reperfusion strategy is timely reperfusion with primary percutaneous coronary intervention (PPCI), ideally within 120 min of STEMI diagnosis. 5,6 Administration of beta-blockers before PCI can decrease ischemic injury due to their impact on reducing myocardial contractility, slowing heart rate, lowering systemic blood pressure, and inhibiting neutrophils function, which in turn diminish reperfusion injury, especially with metoprolol. 7 Current STEMI guidelines adopted early intravenous b-blockade for the STEMI population at the time of presentation before PCI, ensuring no contraindications, no signs of acute heart failure, and the systolic blood pressure is >120 mmHg. In response to the (METOCARD-CNIC) Trial that revealed the beneficial effect of Metoprolol in Cardioprotection through an acute myocardial infarction (MI). 8,9 Metoprolol significantly exhibits a decrease in myocardial infarct size and preserved left ventricular (LV) function, which was demonstrated by magnetic resonance imaging 1-week postinfarction. 10 In addition, long-term left ventricular ejection fraction (LVEF) improvement, fewer indications for cardioverter-defibrillator implantation, and a decrease in heart failure readmissions. 11 This meta-analysis aims to study the effect of early intravenous metoprolol in STEMI before PCI on infarct size assisted by cardio magnetic resonance (CMR) and LVEF at 1-week and 6-month followup periods. Also, we aim to study its safety.

| Study design
We did a meta-analysis intending to determine the efficacy of early intravenous metoprolol in STEMI before PCI on infarct size and LVEF using CMR and LVEF. We also intend to investigate its safety. The protocol of this study is registered on Prospero. The number of registration is CRD42022304100.

| Search strategy
Relevant randomized control trials were located using the search

| Eligibility criteria
The following are the inclusion criteria for this meta-analysis: (1) Randomized control clinical trials are one type of study, (2) STEMI is a type of patient. Patients with anterior STEMI, Killip class-II, and a symptom onset-to-reperfusion period of 6 h, (3) Early IV metoprolol delivery to STEMI patients is one type of intervention. Patients before PCI (4) types of controls: Control group who did not receive metoprolol.

| Exclusion criteria
We excluded cohort studies, case reports, editorials, and animal studies.

| Study selection process
In the initial screening step, two independent researchers (H. G. and N. G.) examined the searched papers' titles and/or abstracts to identify potentially included publications. Second, potential reports will be requested to be recovered. Third, the retrieved reports' whole texts will be evaluated independently by the same researchers. A three-step screening process will determine the study's ultimate inclusion. Any disputes amongst researchers will be handled through dialog during the screening process.

| Data extraction and management
Two independent researchers will use a standardized, predefined, pilottested excel form to extract the following information: the first author's name, year of publication, country, study design, sample size, participant details, treatment and control interventions, duration of intervention, outcome measures, results, and safety data. Additionally, data will be retrieved to quantify the risk of bias (RoB). Dissension will be used to identify and settle discrepancies; data extraction was done by two authors s as a preliminary step and see if they agree.

| RoB and strength of evidence
RoB: ROB 2 tool will be used to assess the RoB.

| Data synthesis
Data will be analyzed using RevMan software 5.4, and sensitivity analysis may be used. Results will be presented in a fixed model if no heterogeneity was detected and a random model if significant heterogeneity was detected. Finally, 16 studies were included for the systematic review, and eight clinical trials were included in the meta-analysis after the full-text screening, as shown in the preferred reporting items for systematic reviews and meta-analyses ( Figure 1). A summary of the studies is shown in Table 1.
Major adverse cardiac events (MACE), death, heart failure admission, reinfarction, and malignant ventricular arrhythmia adverse events were all reported in 5, 4, 2, 5, and 4 studies, respectively. The adverse events were pooled at 6 months; only one study reported adverse events at 60 months. The overall RoB was low in 6 studies and high in 2 of the included studies, as shown in Figure 2.
The total number of patients included in the study is 1888 patients, 936 patients in the Metoprolol group, 952 patients in the control group, and other baseline data are shown in Table 2.
F I G U R E 1 PRISMA flow diagram. PRISMA, preferred reporting items for systematic reviews and meta-analyses When dividing the overall cohort of patients in quartiles of GCS and GLS, there were significantly fewer patients in the first quartile (i.e., the worst LV systolic function) who received early intravenous metoprolol compared with control patients at 1 week and 6 months (p < .05 for GCS and GLS at both time points).

| LVEF (%)
The pooled effect showed a statistically significant association between

| DISCUSSION
The β1-adrenergic-receptor antagonist such as metoprolol is potentially beneficial in patients with acute myocardial infarction (MI) as they act mainly on cardiomyocytes and decrease the oxygen demand of the myocardium by reducing heart rate blood pressure, and contractility. Some experimental studies also demonstrated that they significantly decrease the risk of ventricular fibrillation. Thus, relative risk reduction in sudden cardiac death has been an overall effect of β1-adrenergicreceptor antagonists, demonstrated by some clinical trials. 13 There is evolving evidence that β1-adrenergic-receptor antagonists effectively reduce the infarct size in acute MI patients if given before pPCI and the reduction in mortality.
The mechanism behind reducing infarct size with selective β1adrenergic agonists such as Metoprolol is somewhat unclear.
However, it is most likely attributed to decreasing the inflammation by impairing neutrophil recruitment and neutrophil-platelet interaction, thus preventing microvascular obstruction. 2 Here, we report outcomes from a patient-pooled metanalysis comparing patients with STEMI undergoing pPCI receiving early intravenous β1-blocker therapy with the control group who did not receive the therapy. We are also comparing the safety of beta-blocker therapy before pPCI. Our results show that the use of Metoprolol before pPCI was associated with a reduction in the percentage of infarcted myocardium, decreased LVESV, and includes patients with frank heart failure or pulmonary congestion.
When primary PCI was being used for reperfusion in STEMI, the effect of β-blockade was further analyzed in a limited and nonrandomized fashion by CADILLAC and PAMI trials in two post hoc retrospective investigations. Their study suggested that the administration of β-blockers immediately before reperfusion by pPCI resulted in lower mortality when compared to its initiation after reperfusion or no administration at all.
However, the effect of preperfusion β-blockade on infarct size was reported neither in CADILLAC nor in the PAMI trial. 15,16 It is well established that infarct size predicts post-infarction mortality. Therefore, treatment with oral β-blocker within 24 h of a STEMI is a class-IA indication. Although experimental studies have reduced infarct size after IV β1-blockade, their use is still not encouraged. Borja Ibanez et al. 8 conducted a randomized, controlled parallel-group, observer-blinded clinical trial of early prereperfusion metoprolol administration in STEMI to study its effects on cardioprotection during acute MI (METOCARD-CNIC trial) by comparing the pre-versus postreperfusion β-blocker initiation in STEMI. This study revealed that in anterior STEMI patients undergoing primary PCI, administration of early intravenous metoprolol before reperfusion decreases infarct size and increases LVEF. This trial also showed that early intravenous metoprolol was safe and did not increase the cardiac events' incidence during admission.
Similarly, Vincent Roolvink et al. 12 published a randomized, double-blind, placebo-controlled trial that studied the effect of early IV β-blocker before pPCI in a general STEMI population (EARLY-BAMI trial). In contrast to the METOCARD-CNIC trial, this study concluded that Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events; however, early intravenous Metoprolol before pPCI was not associated with a reduction in infarct size.
Thus, there is a discrepancy in the efficacy of Metoprolol between the METOCARD-CNIC trial and the EARLY-BAMI trial.
In the METOCARD-CNIC trial, CMR revealed a reduction in infarct size at 1 week and 6 months using early intravenous βblockade. In contrast, no reduction in infarct size was noted at 1 month in the EARLY-BAMI trial. This discrepancy can be attributed to the difference in dose of IV Metoprolol used in these studies and the timing of dose administration or most likely resulted from a smaller infarct size in the EARLY-BAMI trial, making it less likely to show a reduction with early β-blocker use. 17 Our study is limited by some RoB in two of the included studies in the analysis.

| IMPLICATIONS OF THE STUDY
The results of this study can be interpreted in clinical practice by adding early intravenous metoprolol before PCI in STEMI to the guidelines, as it revealed its significant effect in reducing infarct size and increasing LVEF%.

| CONCLUSION
Our study showed that early intravenous Metoprolol before pPCI was associated with reducing the percentage of infarcted myocardium, decreased LVESV, and increased LVEF % at 1-week follow-up.
Still, there was no significant difference in LVEDV and LV mass between the two groups. However, at 6-month follow-up, there was a significant association between the Metoprolol group and decreased LVEDV, decreased LVESV, reduction in myocardial infarct (% and gram), and increased LVEF%. The study also showed a statistically significant association between the Metoprolol group and Decreased MACE, decreased heart failure admission, decreased reinfarction, and decreased malignant ventricular arrhythmia. More multicenter randomized clinical trials are needed to support our findings.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
All data were analyzed and uploaded as Supporting Information Material.