Sex‐gender disparities in nonagenarians with acute coronary syndrome

Abstract Background Acute coronary syndrome (ACS) remains one of the leading causes of mortality for women, increasing with age. There is an unmet need regarding this condition in a fast‐growing and predominantly female population, such as nonagenarians. Hypothesis Our aim is to compare sex‐based differences in ACS management and long‐term clinical outcomes between women and men in a cohort of nonagenarians. Methods We included consecutive nonagenarian patients with ACS admitted at four academic centers between 2005 and 2018. The study was approved by the Ethics Committee of each center. Results A total of 680 nonagenarians were included (59% females). Of them, 373 (55%) patients presented with non‐ST‐segment elevation ACS and 307 (45%) with ST‐segment elevation myocardial infarction (STEMI). Men presented a higher disease burden compared to women. Conversely, women were frailer with higher disability and severe cognitive impairment. In the STEMI group, women were less likely than men to undergo percutaneous coronary intervention (PCI) (60% vs. 45%; p = .01). Overall mortality rates were similar in both groups but PCI survival benefit at 1‐year was greater in women compared to their male counterparts (82% vs. 68%; p = .008), persisting after sensitivity analyses using propensity‐score matching (80% vs. 64%; p = .03). Conclusion Sex‐gender disparities have been observed in nonagenarians. Despite receiving less often invasive approaches, women showed better clinical outcomes. Our finding may help increase awareness and reduce the current gender gap in ACS management at any age.

Conclusion: Sex-gender disparities have been observed in nonagenarians. Despite receiving less often invasive approaches, women showed better clinical outcomes.
Our finding may help increase awareness and reduce the current gender gap in ACS management at any age.

| INTRODUCTION
Over the coming years we shall witness a progressive increase in the aging of the population that will lead to several social and medical challenges. In the field of cardiovascular diseases, aging causes a significant clinical heterogeneity in which sex differences play a key role.
Acute coronary syndrome (ACS) remains one of the leading causes of morbidity and mortality for women, and increases with age. Nevertheless, older women continue to be underrepresented in clinical trials and their management and outcomes are underexplored. 1 This fact is even more relevant in patients with extreme age, such as nonagenarians, who are usually excluded from the main clinical trials because a prolonged follow-up may be compromised by limited life expectancy.
However, the nonagenarian population will become clinically and numerically relevant in our daily routine practice in the near future and data about their prognosis in ACS context is scarce, especially in women. It is expected that female life expectancy will break the 90-year barrier by 2030, a level that was deemed unattainable by some at the beginning of the 21st century. 2 Therefore, there is an unmet need regarding ACS in this fast-growing and predominantly female population. The aim of this study was to compare sex-based differences in ACS management and long-term clinical outcomes between women and men in a cohort of nonagenarians. ST-segment elevation myocardial infarction (STEMI) percutaneous coronary intervention (PCI). The study was approved by the Ethics Committee and adhered to the principles outlined in the Declaration of Helsinki. All data were obtained by a retrospective review of cases using standardized report forms (Appendix S1 admitted with an ACS were classified in STEMI or non-ST-segment elevation ACS (NSTE-ACS), where unstable angina was included, according to current clinical practice guidelines 3,4 and fourth definition of myocardial infarction. 5 The following outcomes were evaluated: mortality, recurrent myocardial infarction, stroke, and major bleeding. Cardiovascular mortality was defined as any death due to proximate cardiac cause (MI, low-output failure, fatal arrhythmia), unwitnessed death, stroke, cardiovascular hemorrhage, death of unknown cause, and all procedure-related deaths, including those related to concomitant treatment. 6 Recurrent myocardial infarction was defined as any myocardial infarction according to the World Health Organization's extended definition. 7 Stroke was defined as focal neurologic deficit lasting ≥24 hours or focal neurologic deficit lasting <24 hours with imaging findings of acute infarction or hemorrhage. 8 Major bleeding was defined as Bleeding Academic Research Consortium score ≥ 3. 9 The primary endpoint was sexbased differences in ACS management. The second endpoints were 1-year all-cause mortality by sex. Long-term survival was compared between patients undergoing PCI and those managed with medical treatment alone by sex. Acute kidney injury stage 3 45 (7) 18 (7) 27 (7) .90

| RESULTS
"There was a non-significant tendency to perform less emergent catheterization in women compared to men (48% vs. 41%; p = .07).
These differences are mainly driven by the STEMI group (66% vs. 55%; p = .06). Regarding this, women were less likely than men to undergo a PCI (40% vs. 31%; p = .01), mainly in the STEMI group with a rate of subsequent PCI lower in women (60% vs. 45%; p = .01). These differences were not found in the NSTE-ACS group as Figure 1 shows.
Angiographic findings and interventional procedures are detailed in Table S2. No differences were found in catheterization access between groups, being the radial access predominant in both. There were no significant differences between the groups in terms of the TIMI flow grade III after the procedure (93% vs. 84%, p = .05). No differences were found in the medical treatment at discharge (Table S3).
A comparison of clinical outcomes between the women and men groups is presented in Table 2

| DISCUSSION
There are two main findings of our study. First, nonagenarian women were less likely to undergo an emergent catheterization compared to men, mainly in a STEMI context. Second, coronary revascularization in women was associated with a lower risk of 1-year all-cause mortality compared to men even after sensitivity analysis.
Cardiovascular disease is the leading cause of death in women in developed countries and its incidence is increasing in developing countries, with ischemic heart disease being the main etiology. 10 Despite the proven efficacy of coronary revascularization, many studies have shown that women are less likely to be referred for revascularization in ACS in different contexts: chronic coronary syndrome, NSTE-ACS, and STEMI. 11 On the other hand, older patients and women are underrepresented in contemporary ACS trials, since the development of observational studies is necessary to measure the real impact of ACS in this subgroup. 12 In our study, female nonagenarians admitted for ACS were treated significantly less often with an invasive approach compared to men, leading to lower revascularization rates, which is significant in the STEMI group. This sex-gender disparity in ACS has been previously described mainly in young populations, as shown by the study VIRGO primary PCI is recommended in STEMI regardless of age and sex. 3 To the best of our knowledge, our study is the first where these sexgender differences are evaluated in a fast-growing and predominantly female population, such as nonagenarians.
A higher burden of frailty characteristics observed in women may influence physicians to adopt less invasive strategies. Subsequently, attending medical staff may have selected a non-invasive approach due to less anticipated life expectancy. In our study, frailty, measured as the presence of disability and/or cognitive dysfunction, could influence clinical decisions in women. It has been broadly reported that women at any age have a higher frailty index compared to men. Nevertheless, their life expectancy used to be longer than men. This inverse association between health and longevity is known as the morbidity-mortality paradox. 19 This phenomenon is not fully understood, but hypotheses include higher self-reported deficits, 20 more diseases that affect quality of life rather than mortality, and higher physiological reserve in women compared to men. 21 Psychosocial factors, such as healthcare utilization and self-reported behaviors have also been implicated in the morbidity-mortality paradox. 22 On the other hand, another possible explanation for the lower intention of coronary intervention in women could be a higher rate of understanding of postprocedural complications in this group. Several studies have demonstrated a higher rate of in-hospital complications and higher rates of bleeding in women, but these sex differences disappear after adjusting for different comorbidities 13 and the use of appropriate antithrombotic treatment and vascular access. 23 Awareness of cardiovascular disease (CVD) among women has improved over the past 15 years, but awareness of atypical symptoms remains low. 24 This might be conducive to misdiagnosis, resulting in a delay in receiving appropriate acute treatments for ACS, including a coronary angiogram and subsequent PCI if indicated. This conservative approach in the female group compared to men could be explained by the wrong perception that ischaemic cardiac symptoms, often less specific in women, are related to other pathologies. 25 The use of a systemsbased approach to STEMI care may help reduce sex disparities and improves STEMI care and outcomes in women, regardless of age. 26

| STUDY LIMITATIONS
The main limitation of this study is its observational design, which implies an inherent selection bias. Moreover, it is difficult to capture and control all potential confounders when using a registry. Despite the use of a propensity-matching score, we cannot control for all potential confounders when using data from a registry. Therefore, the purpose of the study is exploratory, and our results should be considered as hypothesis-generating. In addition, the sample size may lack the power to detect other statistically significant differences in outcomes between groups. Also, we lacked data regarding cardiac rehabilitation reference at hospital discharge and during follow-up.
Therefore, we cannot compare cardiac rehabilitation reference rates at hospital discharge between groups.

| CONCLUSION
In conclusion, sex-gender disparities have been observed in nonagenarians. Despite receiving less often invasive approaches, women showed better clinical outcomes. This finding may help increase awareness and reduce the current gender gap in ACS management at any age.