A recent study by DeFilippis et al. analyzed the difference in outcomes between men and women who experienced a myocardial infarction at young age [
1]. All-cause death appeared to be significantly more frequent in young women when compared with men, and female sex was an independent predictor of outcome [
1]. If the data are consistent also in older adults is still unknown. This concept is of paramount importance in the growing population of older adults and its projected to expand in the following years. Recent analyses about sex-based outcomes after PCI demonstrated that women had an increased 5-year risk of death, myocardial infarction, and revascularization compared with men [
5]. However, these analyses did not involve just ACS, but the wide spectrum of coronary artery disease presentation. Furthermore, the analyzed population was collected from randomized clinical trials where older adults were underrepresented; therefore, the mean age of the study population was low (around 66 years vs. 81 years of the present analysis). A previous analysis of LONGEVO-SCA populations underlined that frail octogenarian women had a worse 6-month prognosis, introducing the potential effect of frailty on sex-related outcomes [
20]. Our study is the first study investigating the long-term prognostic role of the intricate relationship between sex and physical performance in a large population of older ACS adults. Crude mortality is higher in women despite no higher rate of comorbidities. As a matter of fact, only a history of hypertension was more common in women. In contrast, other relevant comorbidities, such as diabetes, dyslipidemia, previous MI, history of ischemic heart disease, peripheral artery disease, and the evidence of multivessel coronary artery involvement, were more frequent in men. According to literature data, women resulted in being older and more compromised at presentation. The univariate analysis confirmed the adverse prognostic role of female sex, consistent with the literature, but after adjusting for confounding factors, sex showed a neutral effect in predicting all-cause death. This observation changes when we consider the physical performance as a potential effect modifier of the relationship between sex and mortality. We found that physical performance, as measured by SPPB, was a strong predictor of all-cause mortality, and its distribution between men and women significantly differed, being poor in the latter group. Thus, it is not surprising that after adjustment for SPPB value we observed a paradigm shift in the prognostic role of female sex. Not only did women not have a poor prognosis compared to men, but female sex was a protective factor in older ACS patients with preserved physical performance. These results could be explained considering the important emerging role of physical performance in outcome prediction: as previously reported, physical performance represents a new risk factor in older ACS patients [
8,
9,
13,
14]. The present study demonstrated that this new risk factor overcame sex effect on outcome. These results have several meanings.
First, our study further highlights and reinforces the importance of physical performance assessment in studies involving older adults. Without this crucial parameter, there is the risk of underestimating the differences between groups and misunderstanding the role of a variable or the effectiveness of medical or interventional therapy. Second, our data suggest that the sex-related impact on mortality after MI is age-dependent. While female sex emerged as a negative prognostic marker in younger patients (≤65 years), it seems to be protective in those older and with preserved or mildly reduced physical performance (SPPB value ≥ 8 points). Third, sex is an unchangeable factor, whereas the physical performance status is not. Cardiac rehabilitation and exercise intervention are safe and effective in older ACS patients and can improve SPPB values [
11,
12,
21]. Unfortunately, women tend to participate less in exercise programs [
22]. This issue is even more striking considering that female sex may exert a protective effect in subjects with good physical performance and should motivate physicians to support the implementation of exercise programs in women after ACS.
Study limitations
Our study suffers from some limitations. First, this is a not prespecified post hoc analysis from three different and independent studies performed for different primary aims. Thus, the present findings should be considered hypothesis-generating and should be confirmed by other independent larger studies. Second, physical performance was only assessed with SPPB. Therefore, we are not able to quantify the benefit of this scale compared to other tools in this large population. However, previous studies demonstrated that SPPB had a better prognostic role than other frailty tools in several populations, including older ACS adults [
16,
17]. Third, although our dataset was extensive and complete, we may not exclude the presence of potential confounding factors not captured in our analysis. This is a crucial point, because older ACS patients are a peculiar population where several factors may play a role and may show a different weight as compared to that of younger populations. Fourth, the LONGEVO SCA study was focused on ACS patients without ST-segment elevation at hospital admission. Finally, the recruitment of patients was performed in the cardiology units of two countries (Italy and Spain). Therefore, our findings require further confirmation in a larger scenario.
Conclusions
In a large real-life population of older ACS adults, after correction for clinical features and physical performance status (namely SPPB values), female sex was not related to adverse prognosis in terms of all-cause death. On the contrary, we found that female sex played a protective role in older ACS patients with preserved physical performance.