ST-Elevation Myocardial Infarction as a First Event

Sex- and Age-Related Mortality

Background: Survival after ST-elevation myocardial infarction (STEMI) as a first event in Germany was analyzed.

Methods: Adults with a first-event STEMI were included for analysis on the basis of insurance data from a German health insurance provider (AOK; approximately 26 million members; median follow-up 48.5 months). The primary endpoints were 30-day mortality, reinfarction or death, major adverse cardiovascular and cerebrovascular events (MACCE), long-term survival for more than 90 days, and overall survival (OS).

Results: STEMI occurred in 17 444 patients (32.8% women). The women were older than the men (median age 74 versus 60 years) and suffered more frequently from cardiovascular comorbidities such as diabetes mellitus, chronic renal disease, and arterial hypertension. Women underwent endovascular or surgical treatment less frequently, but sustained complications (cardiogenic shock, resuscitation) more frequently. After adjustment of the data, women were at higher risk of 30-day mortality (odds ratio [OR] 1.17, 95% confidence interval [95% CI] [1.07; 1.28]), reinfarction or death (hazard ratio [HR] 1.09, 95% CI [1.04; 1.16]), MACCE (HR 1.09, 95% CI [1.04; 1.15]), and poorer OS (HR 1.10, 95% CI [1.04; 1.17]). This effect was especially pronounced in women aged ≤ 60 years. No differences between the sexes were seen among patients who survived for 90 days after the infarction.

Conclusion: In Germany, women ≤ 60 years display a higher 30-day mortality after first-event STEMI, which affects their overall survival. Younger women should receive intensified medical attention after STEMI, especially in the early phase.

In western countries, the incidence of ST-elevation myocardial infarction (STEMI) is estimated at 50 per 100 000 person-years (1, 2). Because cardiovascular disease is among the leading causes of death, timely recognition and optimal treatment of STEMI are of particular importance (3, 4). Differences between the sexes in occurrence, inpatient treatment, and overall survival (OS) after STEMI have been discussed in multiple previous analyses (5, 6, 7, 8). These differences are attributable not only to biological differences but also to sociocultural and behavioral aspects, including lifestyle habits such as physical activity or diet (5). The sexes differ in demographics, with women being older and having more cardiovascular comorbidities at time of STEMI. Furthermore, women and men are treated differently after admission to the hospital, with women less often undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) (9). Overall, women have a poorer outcome than men (6, 10), which is generally explained by their more advanced age and higher rate of comorbidities (11). However, increased in-hospital mortality of women after STEMI is confined to younger patients, which weakens the hypothesis of an effect exclusively attributable to an older and more morbid cohort (7, 12).

Our study analyzed the data of patients experiencing first-event STEMI, with special focus on sex- and age-specific differences in initial presentation, in-hospital treatment, the associated risk factors, and the outcome with regard to reinfarction or death, major adverse cardiovascular and cerebrovascular events (MACCE), and short-term and overall survival.

Methods

The data for a 10-year study period (2008–2018) were obtained retrospectively from the administrative database of the Federal Association of the AOK (Allgemeine Ortskrankenkasse; provider of health insurance to ≈ 26 million members). All cardiac and extracardiac diagnoses made in and out of hospital were encoded using the German Modification of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10-GM) and procedures with the German Procedure Classification (OPS) codes. Drug prescriptions were encoded on the basis of the Anatomical Therapeutic Chemical (ATC) classification. Information on mortality was also deposited in the database. All patients ≥ 18 years old in whom STEMI was recorded as the principal inpatient diagnosis in the period 2014–2015 were selected. STEMI constituted the index event. As a precondition for inclusion, consistent data had to be available covering a preliminary phase of at least 2 years before the index event. Patients with documentation of myocardial infarction (MI), coronary artery disease (CAD), PCI, and/or CABG since 2008 were excluded, as were those whose data were inconsistent and those who had left the insurance company. To avoid double counting of STEMI diagnoses, the initial in-hospital stay with diagnosis of STEMI was merged with any stays in hospitals to which the patient was directly transferred for further care. A detailed flowchart of the selection process and cohort definition can be found in eFigure 1.

eFigure 1

Study design

Patients’ clinical characteristics and comorbidities were identified on the basis of diagnostic codes retrieved from inpatient and outpatient documentation, together with the drugs prescribed within a preliminary phase of 24 months before and during the index event. eTable 1 contains a full list of the ICD-10-GM, OPS and ATC codes.

eTable 1

ICD-10-GM codes and OPS diagnosis and procedure codes relevant for analyses

Data accessibility

Information about the access to health insurance data can be found in the eMethods.

Statistical analysis

The primary outcomes of the analysis were 30-day mortality, OS, long-term survival from > 90 days after the event, reinfarction or death, and MACCE, which include recurrent acute MI, cerebral ischemia, and resuscitation. Multivariable logistic regression models and multivariable Cox regression models with time-dependent covariables for all other primary endpoints were performed to evaluate the association between sex and short- and long-term outcomes. All models took account of sex, age, and the cardiovascular risk factors presented in Table 1. The interaction of sex with all other variables was assessed with the aid of the respective models. The p-values of the odds ratio (OR) of the logistic regression model comparing the sexes, the hazard ratios (HR) of all Cox regression models, and the p-values to test the interaction of all models were jointly adjusted using the Benjamini–Hochberg procedure (13). This served to control the false discovery rate (FDR) with respect to the multiple comparisons. In a secondary analysis, the association between sex and short- and long-term outcomes depending on patient age at the time of STEMI was analyzed. Age was categorized into six groups (< 50, 50–59, 60–69, 70–79, 80–89, > 89 years), and its interaction with sex was added to the models. Drug intake 1 and 2 years after discharge was estimated using the Nelson–Aalen estimate for the cumulative incidence function, with death considered as a competing risk event. FDR-corrected p-values (p^FDR≤ 0.05) were compared with the overall significance level of 5%. Since all other p-values were descriptive and unadjusted, they were interpreted accordingly. Statistical analyses were performed using SAS software V9.4 from SAS Institute Inc., Cary, NC, USA and R version 3.6.0 from R Foundation, Vienna, Austria.

Table 1

Patient demographics at time of STEMI stratified by sex

Results

Overall, 17 444 adults were admitted to the hospital with first-event STEMI within the 2-year study period. Women accounted for 32.8% of cases (n = 5714). They were older than the men (women: median 74 years, interquartile range [IQR] 22; men 60 years, IQR 19). Unadjusted demographic data of the analyzed patients, stratified by sex and age, are shown in Table 1. Women more often presented clinical signs of congestive heart failure (New York Heart Association [NYHA] stage IV: 20.0% versus 14.0%). In contrast, the proportion of patients with no relevant restriction of physical exercise capacity was higher in men than in women (NYHA stage I: 66.0% versus 59.3%). Some patients were taking medication for heart failure prior to their first STEMI (eTable 2). Women were receiving this treatment more frequently, corresponding to the higher prevalence (eTable 3). Cardiac comorbidities such as arterial hypertension, diabetes, chronic kidney disease, and atrial fibrillation or flutter were documented more often in women. Nicotine abuse was the only risk factor found in more men than women.

eTable 2

Prescription of drugs for treatment of heart failure after first STEMI within 1 year and 2 years, stratified by sex and age

eTable 3

Prescription of drugs for treatment of heart failure before first STEMI, stratified by sex and age

Table 2 gives an overview of the characteristics of inpatient treatment as well as the outcome after STEMI stratified by age (under or over 60 years) and sex. Both PCI and CABG were performed less frequently in women. Despite the differences in treatment strategies, both sexes benefited equally from treatment (p^int=0.23). Temporary hemodynamic support devices such as intra-aortic balloon pumps and extracorporeal membrane oxygenation were used in similar proportions of men and women. In-hospital complications such as cardiogenic shock, acute renal failure and cardiopulmonary resuscitation were documented more frequently in women. Drug treatment according to the relevant guidelines (14)—platelet activation inhibitors, beta blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), and statins—was prescribed in > 80% of cases in both sexes after STEMI.

Table 2

In-hospital treatment of STEMI index event, stratified by sex

Association between sex and independent risk factors

Independent risk factors for 30-day mortality, long-term survival, overall survival, reinfarction or death, and MACCE in patients after STEMI were examined. The results of the Cox regression analyses for the endpoints are presented in eTables 4a and 4b. Overall, no relevant differences in independent risk profile were observed between women and men. In both sexes, for example, typical cardiovascular risk factors such as diabetes, atrial flutter or fibrillation, and chronic kidney disease emerged as determinants for poorer OS. Cancer was identified as an independent risk predictor with a more pronounced effect in men, perhaps due to the impact of the respective type of cancer on the prognosis of the respective patient. Arterial hypertension and dyslipidemia were not associated with poorer OS after STEMI.

eTable 4a

Cox regression analysis for sex-specific differences in patient risk profile

eTable 4b

Cox regression analysis for sex-specific differences in patient risk profile

Age- and sex-specific impact on the prognosis

After comprehensive adjustment, female sex was associated with a statistically significant higher risk for 30-day mortality (HR 1.17, 95% CI [1.07; 1.28]), MACCE (HR 1.09, 95% CI [1.04; 1.15]), and reinfarction or death (HR 1.09, 95% CI [1.04; 1.16]). Women showed a statistically significant lower OS than men (HR 1.10, 95% CI [1.04; 1.17]; all p^FDR < 0.05). In a separate analysis of long-term survival with exclusion of patients who died within 90 days after STEMI, however, no relevant difference between men and women was determined (HR 0.99, 95% CI [0.89; 1.10]; p^FDR = 0.091) (Table 3). Overall, 25.9% of women died within 30 days compared with 15.1% of men. With regard to long-term survival, specifically women ≤ 60 years had a markedly higher risk for death after first-event STEMI, while this difference between the sexes was not detectable in the age group > 60 years (Figure 1, eFigure 2). For example, at 4 years after STEMI 17.8% of women and 13.7% of men aged 50–59 years had died, but no difference was observed in patients aged 70 to 79 years (39.6% versus 39.1%). After adjustment, women ≤ 60 years still showed a higher risk of 30-day mortality, MACCE, reinfarction or death, and all-cause mortality for every 10-year decrement in age than men of the same age. The sex-specific differences were greater in younger than in older age groups. Considering only patients who survived at least 90 days after STEMI, however, no age group-specific relevant differences in long-term survival were found between men and women (Figure 2).

Figure 1

Kaplan–Meier estimates for overall survival after first STEMI, stratified by sex and age

Figure 2

Adjusted odds/hazard ratios presenting the association of sex with different endpoints depending on age after first event of STEMI, determined by multivariable logistic regression model (30-day mortality) and Cox Regression model including age, sex and patient risk factors

Table 3

Logistic and Cox regression analysis comparing men and women with regard to reinfarction or death, major cardiovascular and cerebrovascular events (MACCE), overall survival, and long-term survival with exclusion of the first 90 days after the index event, respectively adjusted by patient risk profile

eFigure 2

Kaplan–Meier estimates for overall survival after first STEMI, stratified by sex and age

Discussion

Our analysis shows that the demographics of first-event STEMI patients do not differ greatly from other non-selective STEMI cohorts including patients with repeat events (7, 8, 9). Consequently, patients with suspected STEMI should be assessed by clinicians with equal seriousness whether or not coronary heart disease suggesting a new event is known to exist.

Independent risk factors associated with a poorer outcome after STEMI are not dependent on the sex of the patient. Typical cardiovascular comorbidities such as diabetes mellitus and chronic kidney disease were identified as determinants of a poorer outcome in both men and women. Surprisingly, a previous diagnosis of arterial hypertension or dyslipidemia did not predispose to a worse outcome. The reason for this is unclear. The outcome may have been improved by prior diagnosis and treatment of these comorbidities, while undiagnosed arterial hypertension and dyslipidemia contributed to a less favorable course. Although the cause remains to be clarified, this paradox has also been noted in other analyses (10, 15).

Differences between men and women in outcome after STEMI

Women had a lower unadjusted survival probability after STEMI than men. In the present analysis, advanced age and a higher rate of cardiac comorbidities influenced the overall poorer outcome in women.

After adjusting the data for age, the sex-specific differences were greatest in patients ≤ 60 years. The consistently poorer outcome in women is noteworthy in that it persists despite being known from previous analyses (7, 10, 12, 16): In a nationwide German analysis of patients with MI of any kind published by Heller et al. in 2008, there was a difference in 30-day mortality between men and women in the unadjusted data, but not after adjustment for age (16). The data are conflicting, with other reports indicating that young women are particularly at risk: Vaccarino et al. observed in 1999 that only women aged ≤ 75 years showed higher rates of in-hospital death than men of the same age after MI of any kind (7). Although more than 20 years have passed since this analysis, our nationwide data show that young women still have a poorer outcome.

The special feature of the present results is that they come from patients with a first myocardial infarction. In other words, none of the patients included had undergone regular cardiological monitoring. A recent study by DeFilippis et al. examined a selected group of patients ≤ 50 years with a first infarction among whom the women showed higher in-hospital mortality (10). Consistent with our analysis, no sex-specific differences were found in the patients that survived their hospital stay.

An additional finding of the present study is the cut-off age of around 60 years for sex-specific differences, which was determined in a cohort including patients from all age groups. The risk of death for women ≥ 60 years was similar to that for their male counterparts.

Our data should increase physicians’ awareness that women ≤ 60 years represent a risk group and specifically benefit from early optimal medical treatment after an MI.

There are a number of possible reasons for this age- and sex-related phenomenon. Previous analyses suggest that the mechanism underlying MI may differ in young women. It could be due to pathological hemostasis and endothelial function related to diabetes, which may occur in association with female obesity and pregnancy (17, 18). Particularly in pregnancy or after giving birth, the mechanisms underlying STEMI are more frequently plaque erosion with distal embolization, microvascular disease, or coronary artery dissection (5). Moreover, differences in inpatient treatment may impact negatively on the outcome, such as the lower rates of PCI and CABG in women (5, 19). However, an analysis by Cenko et al. demonstrates a higher mortality of young women even after adjustment of the data for PCI (20). This weakens the argument that the outcome of young women is worsened solely by undertreatment.

Strengths and limitations

The present analysis is based on a large set of unselected nationwide data. Due to the mandatory reimbursement system in Germany, the data are characterized by complete documentation and thus high validity. However, coding errors and misclassifications may be present. The retrospective design and the general constraints that apply to the use of administrative insurance data have been described in previous analyses (16, 21). Only patients who arrived at hospital alive or under resuscitation were included for analysis. Preclinical deaths were not taken into account. Furthermore, clinical parameters such as hemodynamic values, laboratory findings, or overall morbidity could not be accounted for. In general, the data concerned are recorded routinely for settlement processes and not explicitly for research purposes. Thus, diagnoses that are of particular relevance for reimbursement may be overrepresented, while financially less relevant diagnoses may have been ignored.

Conclusions

Despite advances in treatment modalities for STEMI and growing awareness of sex-specific differences in treatment and outcome, young women still have a lower survival rate than men in the early phase following STEMI. In the presented selective cohort of first-event STEMI, women ≤ 60 years are particularly at risk. This even has an impact on overall survival. The present study emphasizes the need for optimal drug treatment and close patient observation by the treating physicians especially in the early phase after STEMI in women ≤ 60 years.

Ethics committee approval

Owing to the anonymous nature of the insurance data used, no written consent from the patients was needed. The study was approved by the local ethics committee (reference number 2019–212-f-S) and conducted in accordance with the Declaration of Helsinki.

Acknowledgment

The authors thank the personnel of the AOK for their technical support.

Funding

This work was supported by The Federal Joint Committee, Innovation Fund (G-BA, Innovationsfonds, reference number 01VSF18051). GenderVasc is a cooperation project with the Research Institute of the AOK (WIdO).

Conflict of interest statement
Dr. Freisinger has received reimbursement of congress attendance fees and travel costs from Bayer. She has been paid for giving talks by the University Hospital Münster Academy and the Westphalia–Lippe Medical Association. She has been the beneficiary of study support (third-party funding) from the G-BA Innovation Fund project GenderVasc and from Quantum Genomics.

Prof. Reinecke has been paid for giving talks by Daiichi, BMS, Pfizer, NovoNordisk, and NeoVasc.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 6 December 2021, revised version accepted on 25 February 2022

Corresponding author
Dr. med. Alicia Jeanette Fischer
Klinik für Kardiologie III
Angeborene Herzfehler und Herzklappenfehler bei Erwachsenen
Universitätsklinikum Münster
Albert-Schweitzer-Campus 1
48149 Münster, Germany

Cite this as:
Fischer AJ, Feld J, Makowski L, Engelbertz C, Kühnemund L, Günster C, Dröge P, Ruhnke T, Gerß J, Freisinger E, Reinecke H, Köppe J: ST-elevation myocardial infarction as a first event—sex- and age-related mortality. Dtsch Arztebl Int 2022; 119: 285–92. DOI: 10.3238/arztebl.m2022.0161

►Supplementary material

eMethods, eTables, eFigures,
www.aerzteblatt-international.de/m2022.0161

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