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Vol. 56. Núm. 3.
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Vol. 56. Núm. 3.
Páginas 168-178 (Julio - Septiembre 2021)
Original article
Acceso a texto completo
Sex differences in the management of patients with acute coronary syndrome: A population-based ecological cross-sectional study in Spain
Influencia del sexo en el tratamiento de pacientes con síndrome coronario agudo: estudio poblacional ecológico transversal en España
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Juan Miguel Ruiz-Nodara,b,,
Autor para correspondencia
ruiz_jmi@gva.es

Corresponding author.
, José Luis Ferreiroc,d,, Aida Riberae,f, Josep Ramón Marsale,f, José María García Acuñad,g, Rosa Agra Bermejod,g, Sergio Raposeiras-Roubính, Emad Abu-Assih, Alberto Corderod,i, Vicente Bertomeu-Gonzálezb,d,i, Antonio Chacón Piñeroj, Juan Manuel Nogales-Asensioj, Francisco Marín Ortuñod,k, María Asunción Esteve-Pastord,k, Pedro Luis Sánchezd,l, Francisco Fernández-Avilésd,m,n, Juan Carlos Gómez Poloo, Ana Viana Tejedoro, Albert Ariza Soléc, Juan Sanchisd,p..., David Martí Sánchezq, Damaris Carballeira Puentesq, Manuel Almendro-Deliar, Melisa Santás-Álvarezs, Amparo Valls-Serralt, Íñigo Lozanou, Manuel Anguitav, Ángel CequiercVer más
a Servicio de Cardiología, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
b Facultad de Medicina, Universidad Miguel Hernández, Sant Joan, Alicante, Spain
c Servicio de Cardiología, Hospital Universitari de Bellvitge – IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
d Centro de Investigación en Red en Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
e Servicio de Cardiología, Institut de Recerca Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
f Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
g Servicio de Cardiología, Hospital Clínico Universitario de Santiago, Santiago de Compostela, A Coruña, Spain
h Servicio de Cardiología, Hospital Universitario Álvaro Cunqueiro, Vigo, Pontevedra, Spain
i Departamento de Cardiología, Hospital Universitario de San Juan de Alicante, Alicante, Spain
j Servicio de Cardiología, Hospital Universitario Infanta Cristina, Badajoz, Spain
k Departamento de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain
l Servicio de Cardiología, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
m Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
n Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
o Servicio de Cardiología, Hospital Clínico San Carlos, Instituto Cardiovascular, Madrid, Spain
p Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, and Universidad de Valencia, Valencia, Spain
q Servicio de Cardiología, Hospital Central de la Defensa Gómez Ulla, Madrid, Spain
r Unidad de Cuidados Agudos Cardiovasculares, Unidad de Investigación Cardiovascular, Unidad de Gestión Clínica (UGC) Cardiología y Cirugía Cardiovascular, Hospital Universitario Virgen Macarena, Sevilla, Spain
s Unidad de Hemodinámica, Servicio de Cardiología, Hospital Universitario Lucus Augusti, Lugo, Spain
t Servicio de Cardiología, Hospital Doctor Peset, Valencia, Spain
u Servicio de Cardiología, Hospital de Cabueñes, Gijón, Asturias, Spain
v Servicio de Cardiología, Hospital Universitario Reina Sofía, Córdoba, Spain
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Table 1. Participant registries.
Table 2. Baseline characteristics of patients with acute coronary syndrome stratified by sex.
Table 3. Interventional procedures during patient hospitalization.
Table 4. Analysis of in-hospital and 1-year follow-up events by sex.
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Abstract
Introduction and objectives

Despite evidence of a reduction in the incidence and mortality of acute coronary syndrome (ACS), some studies have highlighted differences in outcomes between men and women. We aimed to explore sex differences in the management and treatment of patients with ACS in Spain.

Methods

This ecological cross-sectional study combined ACS data from 10 Spanish registries (54 centres). Meta-regression analysis was performed using aggregated data of baseline characteristics, interventional procedures, treatments, and events that occurred during hospitalization and one-year follow-up.

Results

Aggregated data from 34605 patients (75.1% men) was included. ST-segment elevation myocardial infarction was the most frequent diagnosis (58.9%) and almost 80% of patients were Killip Class I. Compared to men, women were older (mean age: 71.0 vs 63.3 years) and presented higher rates of hypertension (68.1% vs 51.7%) and diabetes (37.7% vs 26.5%). Women were also less likely to undergo percutaneous coronary interventions, revascularization surgery, and to receive drug-eluting stents during hospitalization. Regarding to antiplatelet therapy, even though indicated, 23.1% of women were not treated with P2Y12 inhibitors (vs 14.2% of men; P<.001); clopidogrel was the most frequently administered agent (> 60%). Significantly higher in-hospital (5.4% vs 3.7%) and 1-year (8.2% vs 4.9%) mortality was observed among women compared to men, which was mainly attributed to cardiovascular causes.

Conclusions

Despite older age and unfavourable risk profile, female ACS patients seem to be suboptimally treated with P2Y12 inhibitors. To reduce mortality associated with ACS, improved prevention and optimized therapeutic approaches are needed.

Keywords:
Acute coronary syndrome
Sex
Registry
Antiplatelet agents
P2Y12 inhibitors
Abbreviations:
ACS
STEMI
Resumen
Introducción y objetivos

A pesar del descenso en la incidencia y en la mortalidad por síndrome coronario agudo (SCA), algunos estudios indican discrepancias en los resultados entre varones y mujeres. Nuestro objetivo fue investigar la influencia del sexo en el tratamiento de pacientes con SCA en España.

Métodos

Estudio ecológico transversal que recogió datos de 10 registros españoles de SCA (54 centros). Se realizó un análisis de meta-regresión con datos agregados de características basales, procedimientos, tratamientos y eventos intrahospitalarios y durante un año de seguimiento.

Resultados

En 34.605 pacientes (75,1% varones), el diagnóstico más frecuente fue infarto agudo de miocardio con elevación del segmento ST (58,9%) y 80% fueron clase Killip I. Las mujeres presentaron mayor edad (media: 71.0 frente a 63.3 años), tasa de hipertensión (68,1% frente a 51,7%) y diabetes (37,7% frente a 26,5%) que los varones. El número de intervenciones coronarias percutáneas, cirugía de revascularización y uso de stent fármaco-activo fueron menores en las mujeres. Respecto a la terapia antiagregante, el 23,1% de mujeres no recibieron inhibidores P2Y12, aun estando indicado (frente a 14,2% de varones; p < 0,001); clopidogrel fue el más administrado (> 60%). La mortalidad intrahospitalaria (5,4% frente a 3,7%) y al año (8,2% frente a 4,9%) aumentó significativamente en las mujeres respecto a los varones, principalmente por causas cardiovasculares.

Conclusiones

A pesar de su mayor edad y perfil de riesgo desfavorable, las mujeres con SCA parecen estar infratratadas con inhibidores P2Y12. Reducir la mortalidad asociada con el SCA requiere una mejor prevención y enfoques terapéuticos optimizados.

Palabras clave:
Síndrome coronario agudo
Sexo
Registro
Terapia antiagregante
Inhibidores de P2Y12
Texto completo
Introduction

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.

MethodsStudy design and objectives

Population-based ecological cross-sectional study that collected aggregated data from ten ACS patient registries across 54 centres in Spain (Table 1 and Table 1 of the supplementary data). The study population was composed of patients (men and women) hospitalized in the participant centres, who had been diagnosed with ACS (ST-segment elevation myocardial infarction [STEMI], non-ST-elevation acute myocardial infarction or unstable angina), and whose data were entered in the corresponding ACS registry. These registries included medical records of demographic data, risk factors and comorbidities, treatments, procedures, and events that occurred during hospitalization and one-year post-discharge. Inclusion or exclusion criteria were not established for the goal of this study.

Table 1.

Participant registries.

Registry  Centres  Recruitment period  Patients  Men  Women 
  n    n  n (%)  n (%) 
VESA study  10  2010–2015  12358  9707 (78.6%)  2651 (21.4%) 
CARDIOCHUS registry  2005–2019  6799  4913 (72.3%)  1886 (27.7%) 
Cardio CHUVI-ACS  NA  6293  4655 (74.0%)  1638 (26.0%) 
SCA San Juan  2008–2019  2234  1651 (73.9%)  583 (26.1%) 
SCAB  2011 and 2016  1761  1289 (73.2%)  472 (26.8%) 
ACHILLES  2014–2015  1717  1225 (71.4%)  492 (28.6%) 
SPARTA  34  2015–2016  1441  1134 (78.7%)  307 (21.3%) 
IPAG-SCA  2013–2015  1214  924 (76.1%)  290 (23.9%) 
LONGEVO-SCA  2016  526  322 (61.2%)  204 (38.8%) 
SCA Gómez Ulla  2012–2019  262  166 (63.4%)  96 (36.6%) 
Total  54    34605  25986 (75.1%)  8619 (24.9%) 

Our primary objective was to identify the proportion of women with ACS who are undertreated with antiplatelet agents (P2Y12 inhibitors). Secondary objectives were determined as male vs. female comparisons in (a) all-cause mortality, (b) cardiovascular-related mortality, (c) interventional procedures, (d) stroke and reinfarction, and (e) bleeding complications.

Study variables

Aggregated data of patient baseline characteristics, bleeding risk, interventional procedures and events were obtained from each registry and used as variables in the analysis.

Baseline characteristics included: sex, age, weight, height, type of ACS (STEMI, non-ST-elevation acute myocardial infarction or unstable angina), Killip Class (I, II, III or IV), cardiovascular risk factors (hypertension, smoking, family history of ischaemic heart disease), comorbidities (cerebrovascular accident or transient ischaemic attack, peripheral artery disease, chronic kidney disease, dyslipidaemia, anaemia, and diabetes), prior treatments, and biochemical parameters (creatinine clearance, haemoglobin and troponin). Patients’ bleeding and ischaemic risk were estimated using the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA guidelines)29 and GRACE (Global Registry of Acute Coronary Events)30 scores, respectively.

Variables related to interventional procedures were catheterization, access site, percutaneous coronary intervention, drug-eluting stent, coronary revascularization surgery and revascularization. Events included all-cause and cardiovascular-related mortality, stroke, reinfarction and bleeding complications, which were measured according the standardized criteria defined by the Bleeding Academic Research Consortium (BARC) in patients receiving antithrombotic therapy, specifically BARC types 2 to 5.31

Statistical analysis

Patient characteristics were evaluated using absolute and relative frequencies (percentages) for categorical variables, while mean and standard deviation (SD) were used for the continuous variables. To estimate the association between sex and binary categorical variables, analysis of binary data was performed. The odds ratio (OR) was used to measure the effect. A meta-regression model was used to find potential associations between variables, determining Wilson's or Fisher's exact test and 95% confidence interval (95%CI). The statistical analysis was carried out using STATA (version 11). A level of significance of α0.05 was considered for the aforementioned analyses.

Ethical statement

Clinical information was obtained from Spanish ACS registry databases. This study was approved by the Ethics Committee for Research with medicinal products (CEIm) of Hospital Universitario de Bellvitge (L’Hospitalet de Llobregat, Barcelona, Spain); ACS registries included were previously authorized by their corresponding research ethics committees. Given that aggregated data was used for the analysis instead of individual patient records, additional informed consent was not required.

ResultsBaseline characteristics

Overall, aggregated data from 34605 patients belonging to 54 centres and ten national registries were collected (Table 1 and Table 1 of the supplementary data). Of these, 75.1% were men and 24.9% were women, with a mean age of 63.3±12.6 years and 71.0±12.6 years, respectively (Table 2). The most frequent ACS in the population was STEMI (58.9%), and nearly 80% of all patients were classified into Killip Class I on admission. Among the risk factors identified, twice as many men as women were smokers (41.9% vs. 23.2%; P<.001), whereas women presented hypertension (68.1% vs. 51.7%; P<.001) and diabetes mellitus more often (37.3% vs. 26.5%; P<.001). In contrast, despite its low frequency, peripheral artery disease was found more often in men than women (8.3% vs. 4.6%; P<.001). In terms of the most frequent comorbidities affecting both sexes similarly, 46.6% of all patients had dyslipidaemia, 20.3% had anaemia and 14.9% had chronic kidney disease.

Table 2.

Baseline characteristics of patients with acute coronary syndrome stratified by sex.

  Men  Women  P  Total 
Patients, n (%)  25986 (75.1)  8619 (24.9)    34605 
Age (y), mean±SD  63.3±12.6  71.0±12.5  <.001  62.2±12.5 
Weight (kg), mean±SD  80.6±13.9  70.0±13.0  <.001  77.9±13.7 
Height (cm), mean±SD  169±157±<.001  165±
Type of ACS, n (%)
STEMI  15801 (60.3)  4566 (54.4)  <.001  20367 (58.9) 
NSTEMI  8314 (32.5)  2945 (35.8)    11259 (32.5) 
Unstable angina  1810 (7.2)  814 (9.8)    2624 (7.6) 
Killip Class on admission, n (%)
Class I  20982 (85.1)  6546 (79.4)  <.001  27528 (79.5) 
Class II  2128 (8.7)  1038 (12.5)    3166 (9.1) 
Class III  691 (2.8)  339 (4.1)    1030 (3.0) 
Class IV  840 (3.4)  333 (4.0)    1173 (3.4) 
Cardiovascular risk factors, n (%)
Hypertension  12352 (51.7)  5669 (68.1)  <.001  18021 (55.7) 
n  24030  8325    32355 
Smoking  10470 (41.9)  1927 (23.2)  <.001  12397 (37.3) 
n  24889  8313    33202 
Family history of ischaemic heart disease  950 (9.5)  313 (8.1)  .213  1263 (8.2) 
n  11237  4170    15407 
Comorbidities, n (%)
CVA or TIA  1280 (5.2)  547 (6.5)  <.001  1827 (5.5) 
n  24887  8325    33212 
Peripheral artery disease  2055 (8.3)  370 (4.6)  <.001  2425 (7.3) 
n  24886  8325    33211 
Chronic kidney disease (CCr <60mL/min)  3034 (14.3)  1160 (16.8)  <.001  4194 (14.9) 
n  21169  6905    28074 
Dyslipidaemia  8283 (46.0)  2939 (50.0)  <.001  11222 (46.6) 
n  18200  5893    24093 
Anaemia  2123 (17.1)  1010 (22.9)  <.001  3133 (20.3) 
n  11327  4113    15440 
Diabetes  5872 (23.7)  2481 (29.8)  <.001  8353 (25.2) 
n  24886  8325    33211 
Insulin-dependent diabetes  444 (26.5)  287 (37.3)  <.001  731 (29.8) 
n  1680  772    2452 
Prior treatments,n (%)
Aspirin  5723 (23.4)  1988 (24.2)  .073  7711 (23.3) 
n  24854  8300    33154 
ADP receptor inhibitors  1425 (5.8)  424 (5.1)  .021  1849 (5.6) 
n  24721  8229    32950 
Oral anticoagulants  1165 (4.9)  578 (6.9)  <.001  1743 (5.3) 
n  24421  8325    32746 
Biochemical parameters
Creatinine clearance (mL/h), mean±SD  84.2±33.6  72.6±30.1  <.001  81.1±32.7 
Haemoglobin (g/L), mean±SD  14.2±2.1  12.9±1.7  <.001  13.8±2.0 
Troponin-positive, n (%)  11593 (83.8)  3958 (77.0)  <.001  15551 (81.7) 
n  13891  5138    19029 
Risk scores, mean±SD
GRACE score (ischaemia)  140.9±38.7  151.1±41.2  <.001  143.8±39.3 
CRUSADE score (bleeding)  22.3±14.7  35.6±16.1  <.001  26.0±15.1 

ACS, acute coronary syndrome; ADP, adenosine diphosphate; CCr, creatinine clearance; CRUSADE, Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines; CVA, cerebrovascular accident (acute stroke); GRACE, Global Registry of Acute Coronary Events; NSTEMI, non-ST-segment-elevation myocardial infarction; STEMI, ST-segment-elevation myocardial infarction; TIA, transient ischaemic attack (ministroke).

Some differences were found in previous treatments regarding the use of adenosine diphosphate receptor inhibitors and oral anticoagulants, although aspirin was administered more often overall (23.3% vs. 5.6% adenosine diphosphate receptor inhibitors vs. 5.3% oral anticoagulants) and similarly across groups. Regarding biochemical parameters, higher creatinine clearance, haemoglobin and positive troponin levels were encountered in men. Conversely, increased ischaemic and bleeding risk, as determined by the GRACE and CRUSADE scores, respectively, were found among women.

Procedures during hospitalization

Procedural characteristics are summarized in Table 3. Catheterization and radial access were performed in the vast majority of patients regardless of sex (88.0% and 87.1%, respectively). However, despite an overall frequency of 81.0%, an 11.8% difference in favour of male patients was observed for percutaneous coronary interventions. Women were also less likely to receive a drug-eluting stent (33.4% vs. 38.6%; P<.001) or undergo coronary revascularization surgery (3.7% vs. 11.9%; P<.001).

Table 3.

Interventional procedures during patient hospitalization.

Procedure  Men n (%)  Women n (%)  P  n (%) 
Catheterization  22625 (90.2)  7211 (86.5)  <.001  29863 (88.0) 
n  25074  8337    33438 
Access
Radial  12618 (87.4)  4273 (86.3)  .237  16891 (87.1) 
Femoral  1655 (11.5)  587 (11.9)    2242 (11.6) 
Other  163 (1.1)  91 (1.8)    254 (1.3) 
n  14436  4951    19387 
Percutaneous coronary intervention  21058 (84.0)  6014 (72.2)  <.001  27072 (81.0) 
n  25074  8329    33403 
Drug-eluting stent  9613 (38.6)  2741 (33.4)  <.001  12354 (37.3) 
n  24925  8218    33143 
Coronary revascularization surgery  921 (11.9)  212 (3.7)  <.001  1124 (5.3) 
n  15412  5687    21090 
Revascularization
Complete  6775 (59.7)  2150 (60.7)  .302  8925 (59.9) 
Partial  4576 (40.3)  1392 (39.3)    5968 (40.1) 
n  11351  3542    14893 
Treatment at discharge

The majority of patients (≥90%) were treated with aspirin and/or statins at discharge (Fig. 1). Frequently used medication included angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (>70% of patients), and P2Y12 inhibitors and beta-blockers (>78% of patients). However, significant variations were encountered between sexes, particularly in the case of P2Y12 inhibitors and beta-blockers: a 7–10% difference was observed in favour of men compared to women. Overall, female patients were less likely to receive all these pharmacological treatments, with the sole exception of oral anticoagulants, which were administered to 10.4% women vs. 7.4% men (P<.001).

Fig. 1.

Medication at discharge by sex. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

(0,38MB).

A total of 23.1% of women (95%CI, 19.6–26.8) appeared to be undertreated with P2Y12 inhibitors despite having this indication (Fig. 2), showing a statistically significant difference compared to men (OR, 14.2%; 95%CI, 13.1–15.3; P<.001). Among P2Y12 inhibitors, clopidogrel was used more often than ticagrelor or prasugrel irrespective of patients’ sex (64.3%, 11.9% and 9.6% in treated men vs. 62.4%, 9.8% and 4.3% in treated women, respectively).

Fig. 2.

Treatment with P2Y12 inhibitors by sex.

(0,08MB).
In-hospital and follow-up events

A comparative analysis of male and female patient aggregated data was performed for mortality (all-cause and cardiovascular-related), stroke, reinfarction and bleeding episodes, both during the index hospitalization and throughout the subsequent 12-month follow-up, as well as for the interventional procedures that patients underwent during hospitalization (Table 4).

Table 4.

Analysis of in-hospital and 1-year follow-up events by sex.

Event  Men n (%)  Women n (%)  P  OR (95%CI) 
Interventionalproceduresa  55201 (59.6)  16705 (38.3)     
n  92598  43656  <.001  0.91 (0.89–0.94) 
Stroke
In-hospital  155 (0.6)  80 (1.0)  .002  1.59 (1.19–2.14) 
n  24687  8133     
1-year follow-up  195 (1.0)  94 (1.5)  .009  1.43 (1.09–1.87) 
n  20472  6416     
Reinfarction
In-hospital  387 (1.5)  156 (1.8)  .222  1.13 (0.93–1.36) 
n  25976  8608     
1-year follow-up  896 (4.2)  317 (4.7)  .429  1.06 (0.92 1.22) 
n  21462  6804     
Bleeding (BARC 2–5)b
In-hospital  195 (2.9)  78 (3.3)  .455  1.11 (0.85–1.45) 
n  6729  2398     
1-year follow-up  801 (11.2)  290 (11.5)  .646  1.03 (0.90–1.19) 
n  7167  2526     
All-cause mortality
In-hospital  553 (3.7)  296 (5.4)  <.001  1.48 (1.28–1.72) 
n  15050  5475     
1-year follow-up  1060 (4.9)  570 (8.2)  .005  1.41 (1.11–1.81) 
n  21658  6955     
Cardiolvascular-related mortality
In-hospital  488 (3.6)  250 (5.0)  <.001  1.41 (1.21–1.65) 
n  13722  4980     
1-year follow-up  483 (4.1)  249 (6.0)  <.001  1.38 (1.18–1.63) 
n  11757  4164     

95%CI, 95% confidence interval; BARC, Bleeding Academic Research Consortium; OR, odds ratio.

a

Interventional procedures included: catheterization, percutaneous coronary intervention, drug-eluting stent, and coronary revascularization surgery. Patients may have undergone one or more interventional procedures. Aggregated data of all procedures performed in the entire population is depicted; individual patient information cannot be extracted.

b

Among the different scores utilized by the registries to measure bleeding, BARC 2–5 classification was the most frequently used in the population.

Overall, an increased frequency of events was observed in female compared to male patients. Significantly higher rates of both all-cause and cardiovascular-related mortality were observed in women compared to men, both during hospitalization (OR, 1.48; 95%CI, 1.28–1.72; and OR, 1.41; 95%CI, 1.21–1.65, respectively; P<.001) and follow-up (OR, 1.41; 95%CI, 1.11–1.81]; P=.005; and OR, 1.38; 95%CI, 1.18–1.63; P<.001, respectively). In all cases, mortality (range: 3.7% to 8.2%) was mainly associated with cardiovascular causes (range: 3.6% to 6.0%). Moreover, interventional procedures were performed significantly less often in women than men, accounting for a 12% difference between sexes.

Bleeding, according to BARC 2–5, was more frequently encountered in inpatients compared to other events, such as reinfarction or stroke, regardless of sex. Whilst stroke was the lowest reported event (≤1.5%), either during hospitalization or thereafter, it occurred significantly more often among women (OR, 1.59; 95%CI, 1.19–2.14; P=.002; and OR, 1.43; 95%CI 1.09–1.87; P=.009, respectively).

Discussion

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

Limitations

Our study has certain limitations that should be taken into consideration, as they could explain the aforementioned discrepancies with previous publications. First, although we have attempted to homogenize data from the ten registries, heterogeneity cannot be completely ruled out. Registries included in this study differed in patient inclusion criteria, particularly for the time of inclusion, which may have partially biased some of the results (e.g. the use of drug-eluting stents and the extremely low percentage of patients using newer and more potent P2Y12 inhibitors, as well as the higher proportion of STEMI cases in our population compared to literature). Second, given the observational nature of this study, inherent differences may be found in some of the variables evaluated. Since individualized patient data could not be analyzed, it is not possible to examine the causality of events. Third, patients may have presented certain clinical features, experienced events (i.e. in-hospital mortality) or undergone interventional procedures that have not been documented. While mortality and reinfarction are variables that could be easily extracted from electronic medical records, some events, such as mild or minor bleeding, are not always reported by the patient or properly recorded. Moreover, the use of different scores hindered data analysis of some variables, such as bleeding complications. The limitations addressed herein may serve to improve data collection on ACS in Spain, which should be driven by an increased effort to register these cases, along with standardization of patient evaluation criteria.

Conclusions

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.

What is known about the subject?

  • ACS is a major cause of mortality and morbidity in men and women, with the incidence expected to increase in the coming years.

  • Women with ACS usually are older at onset, and present atypical symptoms and unfavourable risk profile. Higher mortality rates and bleeding complications have been reported in female compared to male patients.

  • Although the available evidence is mixed, sex-related differences in the management and treatment of ACS could explain women's poorer clinical outcomes.

Does it contribute anything new?

  • This ecological cross-sectional study included aggregated data from 34605 patients (75% men) from 10 ACS registries and 54 centres in Spain.

  • A trend towards a greater burden of risk factors, more comorbidities and bleeding risk was observed in women.

  • Despite being indicated, over 23% of women were not treated with P2Y12 inhibitors at discharge. Clopidogrel was the P2Y12 antagonist most often administered.

  • Women seemed less likely to undergo interventional procedures. Mortality and stroke were significantly more frequent in female patients, both during hospitalization and follow-up.

Funding

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

Conflicts of interest

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.

Acknowledgements

The authors thank Celia Miguel Blanco at MS-C (Valencia, Spain) for editorial support in writing of this manuscript.

Appendix
Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.rccl.2020.10.009.

Appendix A
Supplementary data

The following are supplementary data to this article:

References
[1]
World Health Organization.
Cardiovascular Diseases (CVDs).
(2017),
[2]
A. Timmis.
Acute coronary syndromes.
BMJ, 351 (2015), pp. h5153
[3]
R.W. Yeh, S. Sidney, M. Chandra, et al.
Population trends in the incidence and outcomes of acute myocardial infarction.
N Engl J Med, 362 (2010), pp. 2155-2165
[4]
M. Stramba-Badiale, K.M. Fox, S.G. Priori, et al.
Cardiovascular diseases in women: a statement from the policy conference of the European Society of Cardiology.
Eur Heart J, 27 (2006), pp. 994-1005
[5]
G. Graham.
Acute coronary syndromes in women: recent treatment trends and outcomes clinical medicine insights.
Cardiology, (2016), pp. 101-110
[6]
M. Schmidt, J.B. Jacobsen, T.L. Lash, H.E. Botker, H.T. Sorensen.
25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study.
BMJ, (2012), pp. 344e356
[7]
S. Chakrabarti, J.S. Morton, S.T. Davidge.
Mechanisms of estrogen effects on the endothelium: an overview.
Can J Cardiol, 30 (2014), pp. 705-712
[8]
K. Dudas, G. Lappas, A. Rosengren.
Long-term prognosis after hospital admission for acute myocardial infarction from 1987 to 2006.
Int J Cardiol, 155 (2012), pp. 400-405
[9]
K. Smolina, F.L. Wright, M. Rayner, M.J. Goldacre.
Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study.
BMJ, 344 (2012), pp. d8059
[10]
C. Koopman, M.L. Bots, A.A. van Oeffelen, et al.
Population trends and inequalities in incidence and short-term outcome of acute myocardial infarction between 1998 and 2007.
Int J Cardiol, 168 (2013), pp. 993-998
[11]
S. Dey, M.D. Flather, G. Devlin, et al.
Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events.
[12]
H. Wada, K. Miyauchi, H. Daida.
Gender differences in the clinical features and outcomes of patients with coronary artery disease.
Expert Rev Cardiovasc Ther, 17 (2019), pp. 127-133
[13]
S. Yusuf, F. Zhao, S.R. Mehta, et al.
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
N Engl J Med, 345 (2001), pp. 494-502
[14]
L. Wallentin, R.C. Becker, A. Budaj, et al.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med, 361 (2009), pp. 1045-1057
[15]
S.D. Wiviott, E. Braunwald, C.H. McCabe, et al.
Prasugrel versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med, 357 (2007), pp. 2001-2015
[16]
A. Holm, S. Sederholm Lawesson, E. Swahn, J. Alfredsson.
Gender difference in prognostic impact of in-hospital bleeding after myocardial infarction – data from the SWEDEHEART registry.
Eur Heart J Acute Cardiovasc Care, 5 (2016), pp. 463-472
[17]
J. Oldgren, L. Wernroth, U. Stenestrand.
Fibrinolytic therapy and bleeding complications: risk predictors from RIKS-HIA.
Heart, 96 (2010), pp. 1451-1457
[18]
R. Mehran, S.J. Pocock, E. Nikolsky, et al.
A risk score to predict bleeding in patients with acute coronary syndromes.
J Am Coll Cardiol, 55 (2010), pp. 2556-2566
[19]
D. Radovanovic, P. Erne, P. Urban, et al.
Gender differences in management and outcomes in patients with acute coronary syndromes: results on 20,290 patients from the AMIS Plus Registry.
Heart, 93 (2007), pp. 1369-1375
[20]
E. Freisinger, S. Sehner, N.M. Malyar, et al.
Nationwide routine-data analysis of sex differences in outcome of acute myocardial infarction.
Clin Cardiol, 41 (2018), pp. 1013-1021
[21]
C. Bavishi, S. Bangalore, D. Patel, et al.
Short and long-term mortality in women and men undergoing primary angioplasty: a comprehensive meta-analysis.
Int J Cardiol, 198 (2015), pp. 123-130
[22]
S.S. Lawesson, J. Alfredsson, M. Fredrikson, E. Swahn.
Time trends in STEMI--improved treatment and outcome but still a gender gap: a prospective observational cohort study from the SWEDEHEART register.
BMJ Open, 2 (2012), pp. e000726
[23]
L. Mosca, E. Barrett-Connor, N.K. Wenger.
Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes.
Circulation, 124 (2011), pp. 2145-2154
[24]
P.G. Steg, R.J. Goldberg, J.M. Gore, et al.
Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE).
Am J Cardiol, 90 (2002), pp. 358-363
[25]
O.A. Alabas, C.P. Gale, M. Hall, et al.
Sex differences in treatments relative survival, and excess mortality following acute myocardial infarction: national cohort study using the SWEDEHEART Registry.
J Am Heart Assoc, 6 (2017), pp. e007123
[26]
J.A. Barrabés, A. Bardají, J. Jiménez-Candil, et al.
Pronóstico y manejo del síndrome coronario agudo en España en 2012: estudio DIOCLES.
Rev Esp Cardiol, 68 (2015), pp. 98-106
[27]
I. Ferreira-Gonzalez.
The epidemiology of coronary heart disease.
Rev Esp Cardiol, 67 (2014), pp. 139-144
[28]
I.R. Dégano, R. Elosua, J. Marrugat.
Epidemiología del síndrome coronario agudo en España: estimación del número de casos y la tendencia de 2005 a 2049.
Rev Esp Cardiol, 66 (2013), pp. 472-481
[29]
S. Subherwal, R.G. Bach, A.Y. Chen, et al.
Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score.
Circulation, 119 (2009), pp. 1873-1882
[30]
K.A. Eagle, M.J. Lim, O.H. Dabbous, et al.
A validated prediction model for all forms of acute coronary syndrome estimating the risk of 6-month postdischarge death in an international registry.
JAMA, 291 (2004), pp. 2727-2733
[31]
R. Mehran, S.V. Rao, D.L. Bhatt, et al.
Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.
Circulation, 123 (2011), pp. 2736-2747
[32]
K.A.A. Fox, P.G. Steg, K.A. Eagle, et al.
Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006.
JAMA, 297 (2007), pp. 1892-1900
[33]
F. Sanchis-Gomar, C. Perez-Quilis, R. Leischik, A. Lucia.
Epidemiology of coronary heart disease and acute coronary syndrome.
Ann Transl Med, 4 (2016), pp. 256
[34]
A. Holm, S.S. Lawesson, S. Zolfagharian, E. Swahn, M. Ekstedt, J. Alfredsson.
Bleeding complications after myocardial infarction in a real world population – an observational retrospective study with a sex perspective.
Thromb Res, 167 (2018), pp. 156-163
[35]
M. Valgimigli, H. Bueno, R.A. Byrne, et al.
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
Eur Heart J, 39 (2018), pp. 213-260
[36]
J. Alfredsson, U. Stenestrand, L. Wallentin, E. Swahn.
Gender differences in management and outcome in non-ST-elevation acute coronary syndrome.
Heart, 93 (2007), pp. 1357-1362
[37]
H. Jneid, G.C. Fonarow, C.P. Cannon, et al.
Sex differences in medical care and early death after acute myocardial infarction.
Circulation, 118 (2008), pp. 2803-2810
[38]
K. Szummer, L. Wallentin, L. Lindhagen, et al.
Relations between implementation of new treatments and improved outcomes in patients with non-ST-elevation myocardial infarction during the last 20 years: experiences from SWEDEHEART registry 1995 to 2014.
Eur Heart J, 39 (2018), pp. 3766-3776
[39]
J. Alfredsson, B. Neely, M.L. Neely, et al.
Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes.
Heart, 103 (2017), pp. 1168-1176
[40]
F. Amico, A. Amico, J. Mazzoni, M. Moshiyakhov, W. Tamparo.
The evolution of dual antiplatelet therapy in the setting of acute coronary syndrome: ticagrelor versus clopidogrel.
Postgrad Med, 128 (2016), pp. 159-163
[41]
E.A. Amsterdam, N.K. Wenger, R.G. Brindis, et al.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Circulation, 130 (2014), pp. 2354-2394
[42]
M. Roffi, C. Patrono, J.-P. Collet, et al.
2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
Eur Heart J, 37 (2016), pp. 267-315
[43]
K.R. Kawamoto, M.B. Davis, C.S. Duvernoy.
Acute coronary syndromes: differences in men and women.
Curr Atheroscler Rep, 18 (2016), pp. 73
[44]
J. Schmucker, A. Fach, L.A. Mata Marin, et al.
Efficacy and safety of ticagrelor in comparison to clopidogrel in elderly patients with ST-segment-elevation myocardial infarctions.
J Am Heart Assoc, 8 (2019), pp. e012530
[45]
J.-S. Shin, S.-J. Tahk, H.-M. Yang, et al.
Impact of female gender on bleeding complications after transradial coronary intervention (from the Korean Transradial Coronary Intervention Registry).
Am J Cardiol, 113 (2014), pp. 2002-2006
[46]
J. Yu, R. Mehran, L. Grinfeld, et al.
Sex-based differences in bleeding and long term adverse events after percutaneous coronary intervention for acute myocardial infarction: three year results from the HORIZONS-AMI trial.
Catheter Cardiovasc Interv, 85 (2015), pp. 359-368
[47]
M.P. Bonaca, R.F. Storey, P. Theroux, et al.
Efficacy and safety of ticagrelor over time in patients with prior MI in PEGASUS-TIMI 54.
J Am Coll Cardiol, 70 (2017), pp. 1368-1375
[48]
G. Giustino, R. Mehran, G.D. Dangas, et al.
Characterization of the average daily ischemic and bleeding risk after primary PCI for STEMI.
J Am Coll Cardiol, 70 (2017), pp. 1846-1857

These authors contributed equally to this work.

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