Gender differences in acute myocardial infarction—A nationwide German real‐life analysis from 2014 to 2017

Abstract Background Female sex was reported to be associated with an unfavorable outcome in acute myocardial infarction (AMI). In this nationwide analysis we assessed sex differences in acute outcomes of AMI and recent trends in patient healthcare. Methods We analyzed 875 735 German cases hospitalized with a main diagnosis of ST‐ (STEMI) and non ST‐elevation myocardial infarction (NSTEMI) between January 01 2014 and December 31 2017 regarding morbidity, in‐hospital mortality and treatments. A multivariable logistic regression model was designed to evaluate the use of interventions and their impact on in‐hospital mortality. Results STEMI cases decreased from 72 894 in 2014 to 68 213 in 2017, with 70% assignable to men. Female sex was associated with older age (74 vs. 62 years), and higher prevalence of cardiovascular risk factors such as chronic kidney disease (19.2% vs. 12.5%), hypertension (69.0% vs. 65.0%) and left ventricular heart failure (36.0% vs. 32.1%). In NSTEMI, female sex was also associated with older age (78 vs. 71 years), and higher prevalence of cardiovascular risk factors such as chronic kidney disease (29.7% vs. 23.9%), hypertension (77.4% vs. 74.5%) and left ventricular heart failure (40.5% vs. 36.4%). Overall, 74.3% of female and 81.3% of male STEMI cases received percutaneous coronary intervention (PCI, p < 0.001). In NSTEMI, PCI was performed in 40.8% of female and 52.0% of male cases (p < 0.001). In‐hospital mortality was notably increased in female patients with STEMI (15.0% vs. 9.6%; p < 0.001; OR 1.07; 95% CI 1.03–1.10) and NSTEMI (8.3% vs. 6.3%; p < 0.001; OR 0.91; 95% CI 0.89–0.93) compared to males. Conclusions Our nationwide real‐world data document that in‐patient STEMI cases continue to decrease in women and men. The observed higher in‐hospital mortality in women was largely attributed to a more unfavorable risk and age distribution rather than to female‐intrinsic factors. Women with AMI continue to be less likely to receive revascularization therapies.


| INTRODUCTION
Acute myocardial infarction (AMI) is still among the most common causes of death in men and women in industrialized nations. 1 Differences related to patients' sex have been reported for incidence, symptom presentation, pathophysiological characteristics as well as treatment strategies and outcome. 2,3 However, awareness of the risk for heart disease in women is much lower than in men. 4 Some studies have shown a negative association between female gender and outcome after AMI: specifically women experience more often delays to reperfusion, adverse events such as major bleeding events and complications associated with vascular access. 5,6,7 Many of the mentioned differences regarding therapy and complications have been attributed to the older average age of female patients at onset of AMI. 2,3,7,8,9,10,11 So far, women are mostly underrepresented in guideline-changing cardiovascular disease research, often presenting less than a third of enrolled patients. 12 In numerous studies, the interaction between gender, risk factors and incidence of myocardial infarction remains controversial. 13 Some studies have suggested specific gender-intrinsic-causes even after adjustment for age and other risk factors, 2,8,14 while others have failed to establish an association between gender and mortality. 15,16,17 As the primary objective of this routine-data-based analysis, sex differences of recent nationwide trends in in-patient healthcare and in-hospital outcome of AMI were evaluated. Furthermore, differences between both sexes of the association of comorbidities and inhospital death were investigated to shed additional light on whether the increased mortality in women is due to a more unfavorable comorbidity of women or a potential gender-intrinsic factor.  We identified all cases with a main diagnosis of ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) between Jan 1st 2014 and Dec 31st 2017 (using an ICD code I21* or I22* within 28 days after onset of symptoms). Further, data on concomitant diseases, risk constellations and selected cardiovascular procedures were acquired for sex-specific analysis. Covariables were determined by ICD codes as well, which were only available from inpatient diagnoses codes from the myocardial infarction hospitalization. Further details have been described previously. 18

| Statistics
The analysis covers all in-patient AMI cases in Germany and does not represent a subsample. All analyses were done for STEMI and NSTEMI cases separately. With regard to the primary question of this work, we want do address differences between female and male patients on in-hospital mortality, and differences between both sexes in the association of different factors for death in in-patient STEMI and NSTEMI cases. Furthermore, we want to address different inhospital treatment strategies between female and male sex. Relative frequencies of death, in-hospital stroke, coronary intervention or surgery were tested via two-sided exact Fischer's test or via two-sided Chi-square test, in cases of large amount of data. Multivariable logistic regression analysis for in-hospital mortality was performed to evaluate the association of sex and in-hospital death adjusted by patient's risk profile in a full model (including all patients) and for female and male sex separately. The models included age, diabetes mellitus (DM), chronic heart failure (CHF), chronic kidney disease (CKD), peripheral arterial disease (PAD), atrial fibrillation and/or flutter (Afib), hypertension, previous stroke, dyslipidemia, obesity, smoking, cancer and a disjoint categorical variable (no angiography, diagnostic angiography only without revascularization, PCI, CABG) to take account for different treatment strategies.
In order to address different patients risk profiles between female and male sex, we evaluated the interaction of gender with all other variables in the respective full models. P-values for the test of interaction of all models were jointly adjusted using Benjamini-Hochberg procedure 19 to control the false discovery rate (FDR) with respect to the multiple comparison problem. FDR-corrected p-values p int ≤ .05 will be compared with the overall significance level of 5%.
Unadjusted and FDR-corrected interaction p-values for all models are presented in the supplements (supplemental Table II Table 1 Age was associated with an increased in-hospital mortality in STEMI and NSTEMI in both sexes, but a significant difference between men and women could only be seen in NSTEMI cases (p int < .001).  Figure 4).

| Costs and length of hospital stay
The

| DISCUSSION
In this nationwide real-world setting including all AMI cases from Germany of the years 2014 to 2017, in-patient STEMI cases continue to decrease over the recent past in both, male and female patients. Furthermore, our data showed, that there were not only marked differences in baseline characteristics of in-patient STEMI and NSTEMI cases but also regarding the in-hospital treatment strategies between female and male patients. The manifestation of AMI in female patients occurred on average at an older age compared to men. Higher age and more frequent unfavorable comorbidities of women are discussed as the major cause for the higher in-hospital mortality in comparison to men. Moreover, the American Heart Association recommends to improve the under-representation of women in clinical trials due to the fact that data presented with sex-and gender-specific results are currently lacking in many studies. 20  This trend was driven by a high risk of cardiogenic shock in the prehospital-phase, which is not covered in our analysis. In their analyses, the authors concluded that the trend was age-dependent. 21 A French study analyzed data from 74 389 patients hospitalized with acute myocardial infarction. Female patients had a higher rate of hospital mortality (14.8% versus 6.1%; p < .0001). As in our study, women in the French study were on average older (75 versus 63 years of age; p < .001). 22 Nevertheless, there are also studies without any difference concerning in-hospital mortality due to gender. In a Polish nationwide study cohort of patient with AMI, female sex did not increase the in-hospital mortality (OR 0.97). 23

| Impact of in-hospital treatment
Our results confirm prior studies, 24.25 which showed that women presenting with acute coronary syndrome were less likely to undergo diagnostic catheterization as well as PCI than men although various studies have demonstrated a benefit from PCI for women and an association with a decreased in-hospital mortality. 26,27,28 In our study, the use of PCI was associated with a decreased inhospital mortality in case of STEMI as well as NSTEMI cases in both sexes. In contrast to this, studies such as FRISC-II and RITA-3-trial that concluded that women with NSTEMI do not benefit significantly from an early invasive treatment in comparison to a conservative treatment. 29,30 In addition, a large study with 11 931 consecutive patients who underwent PCI for various indications during 2000-2009, showed that women undergoing PCI for STEMI had higher mortality than men. This could only partially be explained by a difference in baseline characteristics with more frequent unfavorable comorbidities. 31 Female sex was also associated with decreased n-hospital mortality in case of CABG surgery. In the CADILLAC trial, the authors explain the higher mortality in women after interventional treatment by differences in lower body size as well as more unfavorable clinical risk factors. 32  show increased perioperative mortality rate for women than men due to narrower coronary arteries, which may lead to more technical difficulties as well as less complete revascularization and lower success rates compared to men. However, long-term survival turned out to be similar. 34,35,36 One of many possible influencing factors explaining the differences may be a sex bias in the delivery of medical care. This could mean, that women undergo procedures later or men undergo procedures at a time when the disease is significantly less advanced and the outcome due to conservative care might not show a difference.
We also found an association between age and sex: differences

| Impact of costs and length of hospital stay
Both costs and length of stay are influenced by the patient's morbidity, diagnoses and procedures. Furthermore, due to the principles of the German DRG system, the length of the hospital stay has also impact on the costs incurred. Since women received less often interventions, this could be one reason why the total cost of stay was lower than that of men with an average of the same length of stay.

| Strengths and limitations
One of the strengths of the presented data is the large-sized, unselected population of the entire nation which not only represent individual cases but allows us to analyze the real situation. The reliability and validity of the used ICD and OPS codes is high, because they directly impact the hospitals reimbursement. Furthermore, due to this high impact in reimbursement, all diagnostic and procedural codes are independently verified by the MDK (Medizinischer Dienst der Krankenversicherung/Medical Service of the Health Insurance) in more than 20%-30% of cases to assure that they are correct.
However, there are also some limitations of the study. The data were not patient-but case-based, which could result in some patients being counted twice in a year; however, this could only lead to underestimation of in-hospital mortality. In addition, the fact that the database is administrative and not clinical is also a limitation. Another limitation is the fact that the DESTATIS reflects only the hospital stay and any information after discharge is missing. In addition, these administrative data did not contain all clinically important information which may influence the outcome. The high percentage of patients who were coded as having NYHA IV heart failure may seem raise further questions about data reliability and could at least partly be due to the fact that people with heart failure NYHA IV may be transferred to other hospitals more often and are therefore counted twice in our analysis.

| CONCLUSION
Our nationwide real-world data documented that the observed increased in-hospital mortality in female patients could largely attributed to the impact of the more unfavorable comorbidities and age, rather than due to female-intrinsic factors. With regard to standard coronary treatments (either diagnostic coronary angiography or PCI), female sex were associated with a decreased in-hospital mortality in STEMI and NSTEMI cases.
Of note, female patients, and especially older women, received major diagnostic and therapeutic procedures less frequently than men.
Further studies will be needed to determine whether the differences in procedural rates reflect appropriate clinical practice or whether the outcome of women with acute coronary syndrome are negatively affected by these differences. Therefore, it is important that health care providers are made aware of potential sex differences in treatment, particularly in regard to the use of diagnostic catheterization in older patients.

ACKNOWLEDGMENT
Open access funding enabled and organized by Projekt DEAL.