Sex differences in acute myocardial infarction: protocol for an umbrella review

Abstract

Introduction

In recent decades, differences in the risk factors, presentations, management strategies and outcomes of acute myocardial infarction (AMI) between the sexes have emerged. Several systematic reviews and meta-analyses (SMRAs) on this specific topic have been conducted, and an overall assessment of the information available on the subject is needed. The protocol details our proposed methodology for conducting an umbrella review (systematic review of SRMAs) on sex differences related to AMI treatment.

Methods and analysis

An umbrella review will be conducted following the guidelines of the Joanna Briggs Institute. Papers published from database inception until November 25th, 2024, were searched in Ovid Medline, Embase, APA PsycInfo, the Cochrane Database of Systematic Reviews, Epistemonikos and Scopus using controlled vocabulary and text words expressing sex differences AND myocardial infarction. An updated search will be conducted near the end of the umbrella review process to ensure that not recently published SMRAs are missed. No language restrictions will be applied in the database searches, but only SRMAs reported in English will be eligible for inclusion. The inclusion criteria include SMRAs reporting sex differences in outcomes related to AMI treatment among adults. All review steps will be conducted independently by two reviewers. Data will be extracted using a recommended standardised data extraction form. A critical appraisal checklist will be used to assess the risk of bias within the included SMRAs. The findings will be summarised through narrative synthesis using text and tables.

Ethics and dissemination

Ethics approval is not required, as this review will use publicly available data. The results will be disseminated as a peer-reviewed journal article and through national/international conferences.

Trial registration number

PROSPERO, CRD42024561159.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• We developed a comprehensive search strategy across six databases in collaboration with an experienced systematic review librarian.

• Only articles published in English will be included in this study, which may lead to the exclusion of potentially relevant studies available in other languages.

• There is a potential for subjective bias in the evaluation of literature quality.

Introduction

Cardiovascular diseases (CVDs) are the leading cause of mortality globally, posing a profound impact on public health.^{1 2} Yet, the effects of CVDs are not uniform across sexes, and differences have been observed in mortality rates, comorbidities and complications, such as stroke, that indicate higher rates in women than in men.³,⁹

CVD is more complex in women than in men, and sex differences exist in terms of body composition, sex hormones and lipid levels, whereby women have a higher body fat percentage¹⁰ and higher HDL cholesterol than men.¹¹ Although both sexes exhibit many of the conventional risk factors for CVDs, significant sex differences exist. Specifically, a woman’s reproductive history could both disclose and affect her cardiometabolic and cardiovascular trajectories in the short and long term. Furthermore, the menopausal transition is a critical period indicating an acceleration in CVD risk.¹² However, this risk is moderated by several factors, including the timing of menopause (eg, premature menopause), the physiological processes and symptoms associated with menopause, and the treatment strategies employed to manage menopausal symptoms.¹² Additionally, parity and giving birth influence women’s cardiovascular risk, where breastfeeding decreases cardiovascular risk¹²,¹⁸ and a longer duration of lactation (≥2 years) has been shown to reduce the risk of coronary heart disease by 23%.¹⁹ Furthermore, early or late menarche, polycystic ovary syndrome, infertility and adverse pregnancy outcomes such as hypertensive disorders and gestational diabetes may also increase CVD risk in the future.^{12 20}

Some of the sex differences in CVD risk factors are well-established (eg, hypertension, dyslipidaemia and diabetes), and others are sex-specific (eg, premature menopause and pregnancy-related disorders), while others remain less known and recognised (eg, intimate partner violence or poverty).⁸

Sex-specific differences exist in the presentation and pathophysiological mechanisms, affecting the outcome of CVD negatively for women, especially for acute myocardial infarction (AMI) where women may have other and more inaccurate symptom attributes.^{21 22} Differences in the presentation and pathophysiological mechanisms of AMI²¹ may affect the management and outcomes of AMI,²¹²³,³⁰ where women may experience delays in time before treatment, ie, door-to-balloon (D2B) or symptom-to-balloon (S2B),³¹,³⁴ and may be less likely to be treated invasively than men.^{26 27 30} In addition, a greater risk of in-hospital complications has been reported for women, such as bleeding,³⁵ coronary perforation (3.7% vs 2.9%, p<0.001), vascular complications (1.0% vs 0.6%, p<0.001)³⁶ and major adverse cardiovascular events (MACE),^{37 38} in addition to the excess risk for cardiovascular mortality,^{39 40} compared with men.

AMI is defined pathologically as myocardial cell death due to prolonged ischaemia, with the presence of AMI injury detected by abnormal cardiac biomarkers, preferably cardiac troponin, in addition to symptoms of AMI, ECG changes, imaging evidence or intracoronary thrombus detection.⁴¹ Globally, the prevalence of AMI is 3.8% in individuals <60 years and 9.5% among those ≥60 years.⁴² Women with AMI are generally older than men at hospital presentation, with a mean age of 73.9 vs 66.5 years (SD, 12.4 vs 13.2 years) being seen.^{30 43 44} However, in recent decades, the incidence of AMI has increased in young people, especially in women.⁴⁵

Despite these disparities, women remain alarmingly understudied, underrecognised, underdiagnosed and undertreated.⁸ Little is known about prognostic factors and adverse outcomes after AMI for women and the possible sex differences between men and women.^{21 22} Given these disparities, it is important to improve understanding of possible sex differences related to the management and treatment of AMI, both prehospital and in-hospital, including the presentation of AMI and cardiovascular risk, which may influence the health outcome of AMI treatment.

In this umbrella review, we will address these possible sex-related differences related to AMI treatment and provide an overall assessment of the information available. The objective of this umbrella review is to provide a comprehensive summary of sex differences in AMI treatment, from the emergence of symptoms through prehospital and hospital treatment to after-discharge care. The posed research question for this review is What is currently known about sex differences related to AMI treatment among adults? More specifically, we want to investigate the following:

1. Are there any sex differences in clinical outcomes following AMI treatment (eg., complications, functional recovery or mortality)?

2. Do the short-term and long-term outcomes (eg, recurrence of AMI and survival) differ between men and women?

3. Are there any differences in the rates of invasive vs conservative treatment strategies related to sex?

4. What are the reported barriers to timely and equal AMI treatment for men and women?

This protocol details our proposed methodology for conducting the umbrella review. The umbrella review will summarise systematic reviews and meta-analyses (SRMAs) on sex differences related to AMI treatment to guide future investigations.

Methods and analysis

Design and registration

Due to the increasing number of studies and systematic reviews on this topic, we will conduct an umbrella review (systematic review of SRMAs) to provide a comprehensive assessment. An umbrella review can provide a bird’s-eye view of the evidence on the effects of particular risk factors related to AMI treatment, in terms of measures such as ORs.⁴⁶

The umbrella reviews will be conducted in four key steps: systematic literature search and study selection, data extraction, statistical analysis if possible, grading of evidence and interpretation of findings.⁴⁶ The umbrella review will be conducted following the guidelines of the Joanna Briggs Institute (JBI).⁴⁷ To optimise the quality of reporting, this umbrella review protocol was designed using the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols).^{48 49} The completed PRISMA-P checklist is found in online supplemental appendix 1.

The protocol was registered on the International Prospective Register of Systematic Reviews, PROSPERO CRD42024561159.

Eligibility criteria 

In this umbrella review, we will include SRMAs exploring sex differences related to AMI treatment (table 1).

Table 1. Inclusion and exclusion criteria based on PICO.

	Inclusion criteria	Exclusion criteria
Participants (P)	Adults (>17 years) treated for or diagnosed with AMI	Children or adolescents (<18 years) not treated for or diagnosed with AMI
Interventions (I)	NA
Comparison (C)	Sex differences related to the treatment of AMI	Not comparing sex differences
Outcomes (O)	Any outcome related to the treatment of AMI. Primary: complications, mortality and MACE. Secondary: presentation, risk factors, medication, readmission, side effects, recovery rates, etc.	Not reporting outcomes related to the treatment of AMI
Design	Systematic reviews with/without a meta-analysis	Other types of design than systematic reviews with/without a meta-analysis, such as other reviews, protocols, editorials, conference proceedings, grey literature and letters
Language	English	Other languages

AMI, acute myocardial infarction; MACE, major adverse cardiovascular events.

Information sources and search strategy

Systematic searches were conducted in Ovid Medline, Embase, APA PsycInfo, the Cochrane Database of Systematic Reviews, Epistemonikos and Scopus, using controlled vocabulary and text words expressing sex differences AND myocardial infarction, for papers published from database inception until 25 November 2024. An updated search will be conducted near the end of the umbrella review process to ensure that not recently published systematic reviews and meta-analyses (SMRAs) are missed (ie, >1 year after the original search). No language restrictions are applied to the searches, although only English-language publications are eligible for inclusion.

Literature search strategies were developed using medical subject headings (MeSH) and text words related to sex differences in AMI treatment. The search strategy was developed by an expert specialised in systematic review searches. The detailed search strategy is provided in online supplemental appendix 2.

Study records

After removing duplicates, we will upload literature search results to Covidence for collaborative study selection. The screening questions and assessment forms will be developed based on inclusion and exclusion criteria and piloted before full screening.

Screening and data extraction will be conducted in pairs, independently by two of the reviewers (AKB, IL and CT). Disagreement will be solved by discussion or, if necessary, bringing in a third reviewer. A standardised data extraction form will be used to extract data from each included SRMA.⁴⁷ The final draft will include specific details relevant to the objective of this umbrella review, collected by AKB, IL and CT.

The extracted information includes the following:

1. Citation details.

2. Objectives of the included review.

3. Type of review.

4. Participant details.

5. Setting and context.

6. Number of databases sourced and searched.

7. Date range of database searching.

8. Publication date range of studies included in the review that inform each outcome of interest.

9. Number of studies, types of studies and country of origin of studies included in each review.

10. Instrument used to appraise the primary studies and the rating of their quality.

11. Outcomes reported that are relevant to the umbrella review question.

12. Method of synthesis/analysis employed to synthesise the evidence and

13. Comments or notes the umbrella review authors may have regarding any included study.

Data items

Available data on PICO items, such as age, sex, cardiovascular risk factors, presentation of AMI such as symptoms and clinical findings (ie, ECG results and plasma levels of cardiac troponins), S2B and D2B time, diagnostic procedures, treatments during hospitalisation and after discharge, will be collected.

Outcomes and prioritisation

Any outcome related to sex differences in the treatment of AMI. The primary outcomes will be sex differences in complications, mortality (short term and long term) and MACE. The secondary outcomes will be sex differences in terms of presentation, risk factors, medication, readmission, side effects, recovery rates, etc.

Risk of bias in individual studies 

To assess the risk of bias within the included SMRAs, the methodological quality will be assessed independently by two reviewers using the JBI Critical Appraisal checklist for systematic reviews and research synthesis.⁴⁷ The degree of study overlap will be presented accordingly.

The critical appraisal checklist includes the following questions:

1. Is the review question clearly and explicitly stated?

2. Were the inclusion criteria appropriate for the review question?

3. Was the search strategy appropriate?

4. Were the sources and resources used to search for studies adequate?

5. Were the criteria for appraising studies appropriate?

6. Was critical appraisal conducted by two or more reviewers independently?

7. Were the methods used to combine studies appropriate?

8. Was the likelihood of publication bias assessed?

9. Were recommendations for policy and/or practice supported by the reported data?

10. Were the specific directives for new research appropriate?

Data synthesis

A systematic narrative synthesis will be provided with the information presented in the text and tables to summarise and explain the characteristics and findings of the included studies.

Patient and public involvement

None.

Ethics and dissemination

As the study uses publicly available data, ethics approval is not required. The results will be disseminated as a peer-reviewed journal article and through national/international conferences.