To ensure transparent reporting, this systematic review and meta-analysis follow the PRISMA guidelines[10] and the MOOSE group's reporting guidelines[11] for observational studies in epidemiology. The research protocol has been registered with PROSPERO, the international prospective register of systematic reviews, under registration number CRD42022300242.

PubMed, Google Scholar, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched systematically for articles in the English language between the time when severe acute respiratory syndrome coronavirus 2 was declared a Public Health emergency of international concern-PHIEC (January 2020) up until February 2022. We used the following keywords: STEMI, fibrinolysis, and COVID-19. We utilized minimum keywords to maximize the initial scope of research in order to ensure the largest number of articles recorded. Complete search strategies used for all electronic databases were developed by an experienced librarian and are reported in the Supplementary material. Reference mining included scanning reference lists of relevant papers, included studies, and systematic reviews published during the analysis of literature.

Our study population consisted of patients with confirmed STEMI. We included studies that reported the impact of the COVID-19 pandemic on STEMI care. We searched for clinical trials, cohort studies, case-control studies, and case series. Animal studies, expert opinions, literature reviews, news articles, letters, editorials, case reports, guidelines, and any studies that did not mention the timing, population, intervention, and outcomes of interest were excluded.

We imported articles retrieved from the systematic search and exported them to EndNote reference library software (Thomson Reuters), where duplicates were identified and removed. Initially, articles were screened based on titles and abstracts by two independent reviewers (H.A.H. and E.P), then filtered relevant articles underwent full-text screening by another two reviewers working independently (H.A.M. and A.B.J). Another reviewer (A.K.) was consulted for decisions regarding any discrepancies during screening.

Data were extracted in a standardized data extraction form. We extracted data related to the following: (1) Summary of the included studies: Authors, year, timing, country, study design, sample size, inclusion criteria, duration of symptoms to intervention, study arms, and duration of follow up; (2) baseline characteristics of the included patients for regression purpose: Age, gender, race, body mass index, comorbidities, smoking status, and type of STEMI; and (3) the study outcomes as stated below. Any disagreements during data extraction were discussed to reach a consensus.

The Newcastle–Ottawa Scale for observational studies was used by two independent reviewers (M.E. and M.K.K.) to evaluate quality on three diverse characteristics: Selection of study groups, comparability of groups, and ascertainment of the outcome of interest[12]. Each article was given a score that indicated how biased it was. Studies with a total score of seven or above were regarded to have a minimal probability of bias. If a study had a total score of six or less, it was determined to have a significant risk of bias. Disagreements in quality ratings were solved by a third reviewer (A.K.).

We included studies that reported the incidence of the use of fibrinolytic therapy for STEMI patients during the pandemic compared to the timeline before the pandemic. The primary outcomes were the incidence of fibrinolysis and all-cause mortality.

The analysis was performed in a sequence of calculations; the odds ratio (OR) of the incidence of fibrinolysis was calculated, followed by the subgrouping of studies based on significant increase in the incidence of fibrinolysis, no change in the incidence of fibrinolysis, and economic status of the countries where the studies were carried out, respecting the World Bank’s classification of developed and developing countries into high-income and low- and middle-income countries (HICs and LMICs), respectively[13]. The effect sizes and the corresponding 95% confidence intervals (CIs) were calculated from raw data and variability measures or extracted directly from the studies. The outcomes were calculated using the DerSimonian and Laird random-effects model. The Higgin I² test was used to evaluate the heterogeneity between studies, and higher percentages indicated higher heterogeneity. The summation effect measures were calculated as OR with 95%CIs. Statistical significance was set at < 0.05 for all calculations.

Publication bias was assessed using the Begg funnel plot test[14]. Sensitivity analysis was performed by adding and removing studies one after another. Meta-regression analysis was executed for all-cause mortality. Two covariates having significant correlation among all the tested ones were displayed in the results. MetaXL version 5.3 (Epigear) add-on for Microsoft Excel 365 and Review Manager 5.4 was used to perform all analyzes. The statistical methods of the study were reviewed by a biomedical statistician.

A summary of estimated effects and the certainty of each piece of evidence was produced using the GRADE approach (Supplementary Table 1). The GRADE criteria categorize the certainty of evidence as High, Moderate, Low, and Very low. The rating process followed the GRADE manual. GRADEpro GDT was used to construct the certainty of evidence and the summary of findings table.

The process of study selection and the characteristics of the included studies are summarized in Figure 1 and Tables 1 and 2, respectively. A total of 2938 studies were initially identified through database searches, and after removing duplicates, 14 studies were found to be eligible for inclusion in this meta-analysis[15-28]. These studies involved 50136 adult STEMI patients, with 15142 patients receiving fibrinolytic therapy during the pandemic era and 34994 patients receiving standard of care before or during the pre-pandemic era. Our meta-analysis assessed the impact of fibrinolytic therapy on clinical outcomes, particularly the risk of all-cause mortality, in comparison to standard-care before or during the pandemic.

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Figure 1 PRISMA chart displaying the process of search to study selection.

To assess the quality of the included studies, we used the Newcastle-Ottawa Scale for observational studies. Out of the 14 included studies, two were cohort studies, while the remaining 12 were case-control studies. Five studies had a low risk of bias (total score: 7-9), while the remaining studies were found to have a moderate risk of bias (total score: 4-6). None of the included studies had a high risk of bias (total score: 0-3). The detailed quality assessment of each study is provided in the (Supplementary Figure 1). The symmetrical funnel plot (Figure 2) indicated no small study or publication bias.

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Figure 2 No evidence of publication bias. A: When studies have been divided based on the incidence of fibrinolysis; B: When studies have been divided based on the income status of countries. HIC: High-income countries; LMIC: Low- and middle-income countries.

All 14 studies included in this meta-analysis investigated the frequency of fibrinolytic therapy in adult STEMI patients during the COVID-19 pandemic compared to the pre-pandemic era. Our analysis revealed a significantly higher incidence of fibrinolytic therapy during the pandemic [OR: 1.80 (95%CI: 1.18-2.75); I² = 78%; P = 0.00; GRADE: Very low] (Figure 3A). Moreover, we observed that patients treated in LMICs had a higher probability of receiving fibrinolytic therapy [OR: 5.16 (95%CI: 2.18-12.22); I² = 81%; P = 0.00; GRADE: Very low] (Figure 3B).

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Figure 3 Increased incidence. A: Fibrinolysis during the pandemic period; B: Fibrinolysis in low-and middle-income countries as compared to high-income countries. HIC: High-income countries; LMIC: Low- and middle-income countries.

We evaluated all-cause mortality in 13 of the included studies. The increased incidence of fibrinolytic therapy was not found to be associated with an increased risk of all-cause mortality [OR: 1.65 (95%CI: 0.67-4.06); I² = 40%; P = 0.27; GRADE: Very low] (Figure 4). However, patients who received fibrinolytic therapy in LMICs were at a higher risk of all-cause mortality [OR: 1.16 (95%CI: 1.03-1.30); I² = 0%; P = 0.01; GRADE: Very low]. Overall, we found no significant association between the all-cause mortality rate and the incidence of fibrinolytic therapy [OR: 1.09 (95%CI: 0.87-1.37); I² = 58%; P = 0.47; GRADE: Very low] (Figure 5).

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Figure 4 No association between all-cause mortality rate and the incidence of fibrinolysis.

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Figure 5 Increased all cause-mortality rate in low-and middle-income countries compared to high-income countries. HIC: High-income countries; LMIC: Low- and middle-income countries.

Meta-regression of heterogeneity was performed for the outcome of all-cause mortality, as it is one of our primary outcomes and more clinically relevant. Hyperlipidemia (reported in 9 studies[15,17-19,22,23,24-28]) and hypertension (reported in 10 studies[15,17-19,22-28]) were tested as covariates. The meta-regression analysis provide evidence that hyperlipidemia is associated with an increased risk of all-cause mortality (P = 0.001) (Figure 6A). The meta-regression analysis further revealed that hypertension is also a significant predictor of all-cause mortality (P < 0.001) (Figure 6B). These findings suggest that managing hyperlipidemia and hypertension may be crucial for reducing the risk of all-cause mortality.

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Figure 6 Meta-regression plot. A: The significant direct relationship between hyperlipidemia and the risk for all-cause of mortality; B: Meta-regression plot displaying the direct relationship between hypertension and the risk for all-cause of mortality. HLD: Hyperlipidemia; HTN: Hypertension.

This meta-analysis has some limitations that warrant consideration. Firstly, it is possible that the use of diverse fibrinolytic agents might have had an impact on our findings, thus confounding the results. Secondly, some of the outcomes in our study displayed high heterogeneity and wide confidence intervals, indicating low certainty. This could be due to the fact that the results were based on small sample sizes with varied outcomes. Additionally, the restriction of the review to English-language studies might have resulted in the exclusion of data published in other languages, which could have affected the findings.

ST-elevation myocardial infarction (STEMI) is a severe form of coronary artery disease with high morbidity and mortality rates. The preferred treatment is primary percutaneous coronary intervention, but the coronavirus disease 2019 (COVID-19) pandemic led to changes in STEMI management, including the use of fibrinolytic therapy as an alternative treatment.

The COVID-19 pandemic placed a significant strain on healthcare resources and providers, leading to changes in STEMI management. However, the impact of fibrinolytic therapy on clinical outcomes during the pandemic remains largely unknown.

The aim of this systematic review is to examine the significance of the increase in fibrinolytic therapy in adult STEMI patients during the COVID-19 pandemic compared to the pre-COVID-19 era and to assess the impact of this treatment strategy on clinical outcomes, particularly the risk of all-cause mortality, in comparison to patients who received standard-care before or during the pandemic.

This study analyzed the incidence of fibrinolytic therapy and all-cause mortality for STEMI patients during the COVID-19 pandemic compared to the pre-pandemic period. Data synthesis and analysis were performed using the DerSimonian and Laird random-effects model, subgrouping studies based on changes in fibrinolysis incidence and economic status of countries. The study used sensitivity analysis, meta-regression analysis, and Begg’s funnel plot test to assess publication bias and heterogeneity. Statistical significance was set at < 0.05.

This meta-analysis of 14 studies revealed a significantly higher incidence of fibrinolytic therapy in adult STEMI patients during the COVID-19 pandemic compared to the pre-pandemic era. Patients in low- and middle-income countries (LMICs) were more likely to receive fibrinolytic therapy, and those who received it in LMICs had a higher risk of all-cause mortality. However, overall, there was no significant association between the all-cause mortality rate and the incidence of fibrinolytic therapy. Meta-regression analysis showed that hyperlipidemia and hypertension were significant predictors of all-cause mortality, indicating that managing these conditions may be crucial in reducing mortality risk.

The incidence of fibrinolytic therapy for STEMI patients increased during the COVID-19 pandemic, particularly in LMICs. However, there was no significant association between fibrinolysis and all-cause mortality. The findings of this study have important implications for public health initiatives.

Fibrinolytic therapy was more frequently used during the COVID-19 pandemic, particularly in LMICs, but no significant association was found between the incidence of fibrinolysis and overall all-cause mortality.