Cardiovascular diseases are a major health problem that constitute a leading cause of morbidity and mortality for both men and women worldwide.1 Whilst a reduction in the incidence and mortality of cardiovascular diseases has been reported in recent years,2,3 European data indicate that it has not been equal between men and women.4 Accordingly, several studies have reported a greater decline in acute myocardial infarction rates in male compared to female patients, who tend to present more comorbidities than their counterparts.5,6 The older age at acute coronary syndrome (ACS) onset in women, which has been attributed to the protective role of oestrogens against coronary events before menopause,7 could also explain the worse clinical outcomes found in some trials.8–10 Given that atypical symptoms of ACS are encountered more often in women than in men,5,11 this altogether contributes to misdiagnosis and delayed recognition of ischaemia.12

Dual antiplatelet therapy with aspirin and P2Y12 adenosine diphosphate receptor antagonists has long been used in ACS to prevent adverse cardiovascular events or death.13 However, novel antithrombotic therapies developed in recent years have been associated with an increased bleeding risk,14,15 which is particularly pronounced among women.16 In line with previous evidence,17–19 female sex has been postulated as an independent predictor of short-term bleeding after acute myocardial infarction.12,16,20

Inconsistent results have been published regarding the influence of sex on ACS outcomes,11,21–24 which may be explained by the inclusion of populations with different baseline characteristics and/or variability in the methodology used for data analysis.25 Nonetheless, among patients with ACS, sex differences in the management of cardiovascular events and subsequent mortality rates remain a concern nowadays.12 Thus, emphasis should be placed on improving the identification of risk factors, early diagnosis and adequate therapeutic strategies in high-risk patients.

Previous independent studies have provided information on the epidemiology, prognosis and management of ACS in Spain.26–28 With this nationwide ecological study that collects aggregated data from ACS patients from several Spanish registries, we sought to evaluate the impact of ACS and explore sex differences associated with patient characteristics, management, and progression in a real-world setting.

Despite the progress made using intensive therapeutic approaches in line with practice guidelines, which has led to a reduction in in-hospital mortality and associated complications,27,32 an increase in the incidence of ACS is expected over the coming decades in Spain.28 To the best of our knowledge, this is the first analysis carried out with ACS data from Spanish registries. We collected aggregated data from the medical records of 34605 patients with ACS from a total of ten nationwide registries comprising 54 centres. Although an increasing incidence of non-ST-segment elevation – ACS has been previously reported in epidemiology studies,28,33 the most frequent type of ACS among registered patients was STEMI. In line with published evidence,5,20,34 women seemed to be older and to present an overall higher rate of risk factors and comorbidities than men. Hypertension, diabetes mellitus, heart failure and chronic kidney disease, along with older age, have been reported to be more frequent among women.5,20,34

Our analysis indicated that most patients (>86%) underwent catheterization and radial access during hospitalization. Radial over femoral access is recommended by the European Society of Cardiology (ECS) guidelines for coronary angiography and percutaneous coronary intervention, to minimize bleeding in patients with ACS who are treated with dual antiplatelet therapy (evidence class I, level A).35 In contrast, our results suggest that women were less likely to undergo other cardiac procedures, such as percutaneous coronary intervention, use of drug-eluting stents and coronary revascularization surgery, which is consistent with previous evidence.19,36,37 Although the percentage of interventional procedures appeared lower overall than recently reported in Europe,38 which may be related to the use of old registries for our analysis, notable sex-related differences were identified.

For ACS, a dual antiplatelet therapy consisting of treatment with aspirin and P2Y12 inhibitors clopidogrel, prasugrel or ticagrelor, is usually recommended for at least 12 months,39,40 considering shorter durations for patients with high-risk bleeding.41,42 Most patients (>90%) received aspirin and/or statins at discharge. P2Y12 inhibitors and beta-blockers were also highly prescribed for ACS (>78%), although substantial differences could be observed between female and male patients. Despite the indications in current guidelines,39,40 a significant number of women appeared undertreated with P2Y12 inhibitors at discharge (23.1% vs. 14.2% undertreated men). These observations are consistent with results from previous studies,5,25,43 thereby highlighting sex-related disparities in the therapeutic management of ACS patients.

Although clopidogrel has long been used as dual antiplatelet therapy to prevent death or adverse cardiac or cerebrovascular events in patients with ACS,13,44 the novel P2Y12 inhibitors ticagrelor and prasugrel have shown superior efficacy.14,15 Despite the preference for prasugrel and ticagrelor over clopidogrel in current ESC guidelines,35 our results suggest that clopidogrel was the most frequently administered P2Y12 inhibitor in ACS patients, regardless of sex, in Spain. This may be due to the time period when data were collected and the inclusion of aggregated data collected by the individual registries before the establishment of current ECS guidelines, but it could also underscore a failure to prescribe novel antiplatelet agents in our setting. The significantly higher rate of anaemia among women compared to men might have also led to the prescription of more conservative antiplatelet therapies.

Given its association with worse outcomes and mortality rates, bleeding constitutes the most frequent non-ischaemic complication in ACS patients.34 Moreover, the novel antiplatelet therapies that have emerged in recent years have been linked to an increased risk of bleeding in these patients.14,15 Some studies have described female sex as an independent predictor of non-surgery related bleeding.17,18,39,45,46 Likewise, an increased bleeding risk, according to the CRUSADE score, was observed in women compared to men in our study. However, this observation did not translate into a statistically significant difference in terms of the number of bleeding events, either during hospitalization or thereafter. While the incidence of bleeding events from discharge to the end of follow-up was in line with the literature,34 a lower number of in-hospital events, likely due to misregistration and subsequent underestimation, was observed among the ACS population in this study.

Overall, a higher frequency of in-hospital and follow-up events were encountered in women with ACS compared to men, with significantly increased all-cause and cardiovascular-related mortality. Whilst these rates seemed lower than those reported in a recent study of women with STEMI (16.9%) and non-ST-elevation acute myocardial infarction (11.7%) during hospitalization,20 our results support the association between sex and unfavourable outcome in ACS.5,17,18,34,39,45,46 In contrast, no sex-related differences were observed in the frequency of reinfarction or bleeding during follow-up in this patient population. Regarding the risk of ischaemia, which was significantly higher among women at baseline, some studies have reported an increased long-term risk compared to bleeding in patients with prior myocardial infarction treated with P2Y12 inhibitors.47,48 Hence, given the importance of both bleeding and ischaemic events in the patient's prognosis, emphasis should be placed on individual risk assessments in order to adopt preventive strategies and more adequate therapeutic approaches.34,41,42

The results of this ecological cross-sectional study suggest that 23.1% of women with ACS may be undertreated with P2Y12 inhibitors in Spain. Despite current recommendations in clinical practice guidelines on the use of ticagrelor or prasugrel as first-line therapy for ACS, clopidogrel appeared to be the most frequently used antiplatelet agent, regardless of sex. Older age and unfavourable risk profile of women could be associated with increased mortality rates, both during hospitalization and at follow-up. Thus, emphasis should be placed on improved ACS prevention strategies and optimized therapeutic approaches in women. Growing awareness of sex differences in the management and importance of adherence to appropriate treatments are needed to improve both ischaemic and bleeding outcomes in female and male patients with ACS.

This work was sponsored by the Spanish Society of Cardiology (SEC). Funding to perform the study was obtained from an unconditioned grant from AstraZeneca.

J.M. Ruiz-Nodar has received honoraria for lectures from AstraZeneca, Biosensor, Boston Scientific, Medtronic and Terumo. J.L. Ferreiro has received honoraria for lectures from Eli Lilly and Company, Daiichi Sankyo, AstraZeneca, Roche Diagnostics, Pfizer, Abbott Laboratories, Boehringer Ingelheim and Bristol-Myers Squibb, consulting fees from AstraZeneca, Eli Lilly, Ferrer, Boston Scientific, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Bristol-Myers Squibb, and research grants from AstraZeneca. A. Cordero has received honoraria from lectures and consulting fees from AstraZeneca and AMGEN, honoraria for lectures from Bristol-Myers Squibb, and consulting fees from Ferrer Internacional. V. Bertomeu-González has received honoraria from lectures from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Pfizer, LivaNova, Sanofi, and Ferrer Internacional. F. Marín Ortuño has received research grants from Fundación para la Investigación de la Región de Murcia (FFIS) and AstraZeneca, and honoraria from Daiichi Sankyo, Boehringer-Ingelheim and Pfizer-BMS. M. Almendro-Delia has received honoraria for lectures from Eli Lilly and Company, Daiichi Sankyo, Ferrer International, AstraZeneca, Pfizer, Boehringer Ingelheim, Bayer Hispania, and Bristol-Myers Squibb, consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Bayer Hispania, and research grants from AstraZeneca. A. Valls-Serral has received honoraria for lectures and/or consulting from Novartis, AstraZeneca and Boehringer Ingelheim. A. Cequier has received research grants from Abbott Laboratories, Biosensors, Boston Scientific, Medtronic, Biomenco, Cordis, Orbus Neich, and the Spanish Society of Cardiology (SEC), and honoraria from Abbott Laboratories, Biosensors, Medtronic, Ferrer International, Terumo, AstraZeneca and Biotronik.

S. Raposeiras-Roubín is associate editor of REC: CardioClinics. The journal's editorial procedure to ensure impartial handling of the manuscript has been followed.

D. Martí Sánchez has received honoraria from AstraZeneca. A. Ribera, J.R. Marsal, J.M. García Acuña, R. Agra Bermejo, E. Abu-Assi, A. Chacón Piñero, J.M. Nogales-Asensio, M.A. Esteve-Pastor, P.L. Sánchez, F. Fernández-Avilés, J.C. Gómez Polo, A. Viana Tejedor, A. Ariza Solé, J. Sanchis, D. Carballeira Puentes, M. Santás-Álvarez, I. Lozano, M. Anguita declares no conflict of interest.