Major Adverse Cardiovascular Events: An Inevitable Outcome of ST-elevation myocardial infarction? A Literature Review

Major adverse cardiovascular events (MACE) remain the major cause of mortality and morbidity in patients with STEMI (ST-elevation myocardial infarction). The current literature is aimed to analyze the occurrence of MACE following STEMI irrespective of treatment provided, and follow up after the first diagnosis of STEMI. A PubMed search for Studies of STEMI identified 24,244 articles. After applying our inclusion/exclusion criteria, we found out 75 articles of relevance wherein MACE and its components were considered to be the primary endpoint. These 75 articles included eight Cohort Studies, 13 clinical trials including five randomized controlled trials (RCT), one case-control Study, one cross-sectional study, one review article, and 51 other observational studies. Our analysis shows that MACE remains one of the strongest adverse outcomes among STEMI patients. The current literature review found out the incidence of MACE was 4.2 % to 51% irrespective of the mode of treatment, and follow-ups lasting up to 10 years from the time of STEMI diagnosis.


Introduction And Background
ST-elevation myocardial infarction (STEMI) has multiple definitions proposed over time and most of them can inclusively be defined as symptoms of ischemia of the myocardium that presents with the classical electrocardiographic change of elevation of ST-segment at J point and positive cardiac biomarkers above the accepted blood level [1]. Electrocardiographically STEMI can be defined as ST-elevation (STE) of ≥ 1 mm at the J point in 2 contiguous chest and limb leads excluding V2-V3, which must be ≥ 2 mm in men or ≥ 1.5 mm in women [2].
Major adverse cardiovascular events (MACE) has no concrete definition, but over time various definitions have been used in cardiovascular research with MACE selected as primary or secondary end-point. It has been defined by various authors since mid-1990 to include an overlapping range of adverse events [3,4]. Multiple adverse events included in different research as a component of MACE are heart failure, non-fatal re-infarction, recurrent angina pain, re-hospitalization for cardiovascular-related illness, repeat percutaneous coronary intervention (PCI), coronary artery bypass grafting and all-cause mortality [5]. MACE can also include unscheduled coronary revascularization, stroke, re-infarction and all-cause death and mortality [6]. MACE with myocardial infarctions have been assessed in the past and multiple articles have been published regarding specific percentage of patients having MACE after particular medical management or after undergoing certain procedures (like PCI) for both STEMI and NSTEMI. The aim of the study is to quantify the available data on the risk of MACE in patients with STEMI irrespective of the mode of management.

Review Method
Literature was searched in PubMed with parallel strategies based on MeSH subheadings and regular keywords for data collection. Table 1 shows regular and MeSH keywords for literature search.

Total Records 22691
Records selected 1800

Regular keyword-STEMI Major Adverse Cardiovascular Events
Total records 1277 Records selected 178

Total records 276
Records selected 87

articles after applying inclusion/exclusion criteria
A total of 1622 articles from keyword search 'STEMI' were excluded due to lack of outcome of interest "Major Adverse Cardiovascular Events" and removal of duplicates. After a refined search, the total number of articles obtained was 178 free full texts. All 178 free full texts were reviewed and 103 were removed due to one of the following reasons: -Not specifying the disease of interest (those which did not assess for STEMI separately but were rather a composite assessment of STEMI with NSTEMI or ACS as a whole or both) -Case Report or Case Series Studies (as it only assessed for a particular patient in focus) -Meta-analysis -Data Extraction not possible by quality assessment.
Finally, 75 publications in PubMed (with free full text available online) were reviewed, which included: -51 observational studies, among which one specifically identified itself as a prospective observational study.
-One study identified as a cross-sectional study (n=1244) -one as case-control study and -one as a review article [28][29][30].
The maximum number of subjects in a study was 15,628 and the minimum was 8, and the total number of subjects included in all 75 studies was 77,782 [31,17]. Among all 75 studies, 62 studies explained percutaneous coronary intervention (PCI) either as the intervention of choice or as a primary intervention inclusive of other management strategies. Coronary angiography was explained as the investigation of choice in four studies [9,[32][33][34].
All the records reviewed were freely available for review and the citations for the borrowed definitions are available. A qualitative review was performed on the available records after Inclusion/Exclusion to include the relevant disease and population with the required outcome.

Discussion
The analysis performed was aimed at demonstrating how STEMI was related to MACE irrespective of the management strategy. Though MACE was observed with all the modalities of management for STEMI, the strength of association was not assessed. We firmly believe that there are large variations in the number of MACE events when clearly analyzed for different modalities of treatment. We also found out that MACE incidence depends upon the pre-STEMI health status, age, gender, race, co-morbidities of the patient and many other factors which are not yet explored.
The endpoint of study was major adverse cardiovascular outcome which was explained in the reviewed literature as combination of at least one or more of: all-cause mortality/death (37 studies), re-infarction (25 studies), cardiovascular mortality/death (23 studies), repeat revascularization (18 studies), stroke (16 Studies), heart failure (14 studies), non-fatal reinfarction (11 studies), stent thrombosis (eight studies), major bleeding (seven studies), microvascular obstruction (five studies), re-hospitalization for cardiovascular-related illness (four studies), repeat PCI (four studies), non-cardiovascular mortality/death (two studies) and transient ischemic attack (one study) .  Due to the widespread use of PCI, and least number of papers published with other modes of management as the primary treatment modality for STEMI, the study could not explore much in areas of specific management strategies. MACE occurrence following STEMI is unpredictable, but the rate of occurrence could be minimized with appropriate treatment approach and strategy. More studies are needed to analyze the outcomes of different management strategies in lowering the incidence of MACE. Even with new advanced techniques and technologies, comparisons between the new and old strategies in management should be done in order to find out both long and short-term outcomes.

Conclusions
The objective of our study is to review the relationship between STEMI and major adverse cardiovascular events irrespective of the treatment modality. The current literature review concluded that MACE remains one of the strongest adverse outcomes in STEMI patients. The incidence of MACE ranges from 4.2% to 51% irrespective of the mode of treatment, with followup visits ranging from day 0 to 10 years following STEMI. The current literature review has some limitations: the study limits its analysis in terms of age (patients involved were ≥45 years old), gender (no gender-specific analysis was performed), modality of treatment, duration of follow up (none of the literature explained the long term follow up ≥10 years) and many other unexplored factors which can be tested in future studies.

Conflicts of interest:
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