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Archives of cardiovascular diseases
Volume 107, n° 5
pages 291-298 (mai 2014)
Doi : 10.1016/j.acvd.2014.04.005
Received : 7 October 2013 ;  accepted : 10 April 2014
Gender differences in presentation, management and inhospital outcome in patients with ST-segment elevation myocardial infarction: Data from 5000 patients included in the ORBI prospective French regional registry
Différences liées au genre dans la présentation, la gestion et le devenir intra-hospitalier des patients hospitalisés pour syndrome coronaire aigu avec sus-décalage persistant du segment ST : analyse des données de 5000 patients inclus dans le registre prospectif français ORBI
 

Guillaume Leurent a, b, c, , Ronan Garlantézec d, Vincent Auffret a, b, c, Jean Philippe Hacot e, Isabelle Coudert f, Emmanuelle Filippi g, Antoine Rialan h, Benoît Moquet i, Gilles Rouault j, Martine Gilard k, l, Philippe Castellant k, l, Philippe Druelles m, Bertrand Boulanger n, Josiane Treuil o, Bertrand Avez p, Marc Bedossa a, b, c, Dominique Boulmier a, b, c, Marielle Le Guellec a, b, c, Hervé Le Breton a, b, c
a Service de Cardiologie et Maladies Vasculaires, CHU de Rennes, 2, rue Henri-le-Guilloux, 35000 Rennes, France 
b INSERM, U1099, Rennes, France 
c Université de Rennes 1, LTSI, Rennes, France 
d École des Hautes Études en Santé Publique, Rennes, France 
e Centre Hospitalier de Lorient, Service de Cardiologie, Lorient, France 
f CHU de Rennes, SAMU, Rennes, France 
g Centre Hospitalier de Vannes, Service de Cardiologie, Vannes, France 
h Centre Hospitalier de Saint-Malo, Service de Cardiologie, Saint-Malo, France 
i Centre Hospitalier de Saint-Brieuc, Service de Cardiologie, Saint-Brieuc, France 
j Centre Hospitalier de Quimper, Service de Cardiologie, Quimper, France 
k CHU de Brest, Service de Cardiologie, Brest, France 
l EA 4324 – Optimisation des Régulations Physiologiques (ORPhy), UFR Sciences et Techniques, Brest, France 
m Clinique Saint-Laurent, Service de Cardiologie, Rennes, France 
n Centre Hospitalier de Vannes, SAMU, Vannes, France 
o CHU de Brest, SAMU, Brest, France 
p Centre Hospitalier de Saint-Brieuc, SAMU, Saint-Brieuc, France 

Corresponding author at: Service de Cardiologie et Maladies Vasculaires, CHU de Rennes, 2, rue Henri-le-Guilloux, 35000 Rennes, France.
Summary
Background

Gender differences in presentation, management and outcome in patients with ST-segment elevation myocardial infarction (STEMI) have been reported.

Aim

To determine whether female gender is associated with higher inhospital mortality.

Methods

Data from ORBI, a regional STEMI registry of 5years’ standing, were analysed. The main data on presentation, management, inhospital outcome and prescription at discharge were compared between genders. Various adjusted hazard ratios were then calculated for inhospital mortality (women versus men).

Results

The analysis included 5000 patients (mean age 62.6±13years), with 1174 women (23.5%). Women were on average 8years older than men, with more frequent co-morbidities. Median ischaemia time was 215minutes (26minutes longer in women; P <0.05). Reperfusion strategies in women less frequently involved fibrinolysis, coronary angiography, radial access and thrombo-aspiration. Female gender, especially in patients aged<60years, was associated with poorer inhospital prognosis (including higher inhospital mortality: 9% vs. 4% in men; P <0.0001), and underutilization of recommended treatments at discharge. Moreover, excess female inhospital mortality was independent of presentation, revascularization time and reperfusion strategy (hazard ratio for women 1.33, 95% confidence interval 1.01–1.76; P =0.04).

Conclusions

One in four patients admitted for STEMI was female, with significant differences in presentation. Female gender was associated with less-optimal treatment, both in the acute-phase and at discharge. Efforts should be made to reduce these differences, especially as female gender was independently associated with an elevated risk of inhospital mortality.

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Résumé
Contexte

Des différences liées au sexe sont signalées dans la présentation, la gestion et le pronostic des patients hospitalisés pour infarctus du myocarde avec élévation du segment ST (IDM ST+).

Objectif

Déterminer si le sexe féminin est associé à une mortalité intra-hospitalière plus élevée.

Méthodes

Nous avons analysé les données d’ORBI, un registre régional de 5ans concernant les IDM ST+. Les principales données concernant la présentation, la gestion, le devenir intra-hospitalier et le traitement à la sortie ont été comparées en fonction du sexe. Ensuite, nous avons analysé la mortalité intra-hospitalière (femmes vs hommes), avec différentes variables d’ajustement.

Résultats

L’analyse a inclus 5000 patients (âge moyen 62,6±13ans), dont 1174 femmes (23,5 %), qui présentaient des co-morbidités plus fréquentes et étaient 8ans plus âgées que les hommes. Le temps d’ischémie médian était de 215minutes (26minutes de plus chez les femmes). Comparativement aux hommes, les stratégies de reperfusion chez les femmes comportaient moins de fibrinolyse, de coronarographie, d’accès radial et de thrombo-aspiration. Le sexe féminin, en particulier chez les moins de 60ans, était associée à un mauvais pronostic intra-hospitalier (y compris une plus forte mortalité intra-hospitalière : 9 % contre 4 % chez les hommes ; p <0,0001), et une sous-utilisation des traitements recommandés à la sortie. Par ailleurs, la surmortalité intra-hospitalière observée chez les femmes était indépendante de la présentation, des délais de revascularisation et des stratégies de reperfusion (hasard ratio 1,33, intervalle de confiance 95 % 1,01–1,76 ; p =0,04).

Conclusions

Une personne sur 4 patients admis pour un IDM ST+ est une femme, avec des différences significatives dans la présentation. Le sexe féminin est associé à un traitement moins optimal, tant à la phase aiguë qu’à la sortie d’hôpital. Un effort particulier devra être effectué afin de réduire ces différences, d’autant plus que le sexe féminin semble constituer dans cette analyse un risque indépendant de surmortalité intra-hospitalière.

The full text of this article is available in PDF format.

Keywords : Gender, Differences, ST-segment elevation myocardial infarction, Outcome, Mortality

Mots clés : Genre, Différences, Syndrome coronaire aigu avec sus-décalage persistant du segment ST, Pronostic, Mortalité

Abbreviations : CI, HR, MI, ORBI, SAMU, STEMI


Background

Several studies have reported increased inhospital mortality in myocardial infarction (MI) with persistent ST-segment elevation (STEMI) in women when compared with men [1, 2, 3, 4, 5, 6, 7]. Several hypotheses have been put forward to account for this excess female mortality, including more serious co-morbidity, longer time to revascularization or use of ‘less-optimal’ reperfusion strategies. It is, however, not yet clearly established whether female gender is in itself a risk factor for inhospital death in the case of STEMI. The present study is an update on gender-linked differences in the characteristics, means of treatment, mortality and inhospital prognosis of patients admitted for STEMI.

Methods

We used the data from the Brittany Regional Infarction Observatory (Observatoire Régional Breton sur l’Infarctus: ORBI) [8]. Brittany is an administrative Region with a population of 3.2 million and nine interventional cardiology centres (see list in Appendix A), covering an area of 34,023km2. ORBI prospectively includes all patients admitted to any of the nine centres for STEMI (final diagnosis) within 24hours of symptom onset. Demographic and electrocardiographic data, treatments, time intervals and inhospital events are recorded prospectively. Overall ischaemia time is defined as the time between symptom onset and initiation of reperfusion: balloon inflation, in the case of primary angioplasty, or administration of fibrinolytic treatment. All patients registered by ORBI between 01 July 2006 and 31 August 2011 were included in the present analysis.

Statistical analysis

Qualitative data are expressed as percentages and quantitative data as means±standard deviations, except for times, which are expressed as medians (range). Multiple imputation was performed to take into account missing data [9]. As a first step, univariate analysis according to gender, clinical characteristics, time to revascularization, revascularization strategy, inhospital prognosis and discharge prescription was performed. Student's (or Wilcoxon's, as appropriate) and Chi2 tests were used for quantitative and qualitative data, respectively. In a second step, inhospital mortality was analysed according to gender, using a Cox model. The association is presented as a hazard ratio (HR) (95% confidence interval [CI]). Various models were constructed according to adjustment strategy: model 1, unadjusted; model 2, adjusted for patient characteristics (age, diabetes, arterial hypertension, active smoking, anterior STEMI location, three-vessel or common left main coronary disease); model 3, adjusted for the variables of model 2 and for overall ischaemia time; and model 4, adjusted for the variables of model 3 and for revascularization variables (coronary angiography, primary angioplasty, radial arterial approach, thrombo-aspiration, glycoprotein IIb/IIIa inhibitor administration, fibrinolysis).

The significance threshold was systematically set at 5%. Statistical analysis used SAS® software, version 9.1 (SAS Institute Inc., Cary, NC, USA).

Results

Over the study period, 5000 patients (mean age 62.6±13years) were included in ORBI; 1174 (23.5%) were female. The main patient characteristics, coronary disease and MI data are presented according to gender in Table 1. Emergency myocardial revascularization was performed in 4344 patients (87%): 3583 (71%) by primary angioplasty and 761 (15%) by fibrinolysis.

The initial emergency call was made using the dedicated emergency telephone number 15 (emergency medicalized ambulance service [Service d’Aide Médicale Urgente ; SAMU]) for 40% of female versus 44% of male patients (P =0.004). Electrocardiography, when performed before hospital admission, showed significant ST-segment elevation in 88% of female versus 95% of male patients (P =0.03). The SAMU provided preadmission treatment in 55% of female versus 61% of male patients (P <0.001). Finally, direct access to the catheterization laboratory in the case of primary angioplasty was available for 57% of female versus 66% of male patients (P <0.0001).

Median overall ischaemia time was 215minutes (63–1530minutes) and was significantly longer for female patients (235 vs. 209minutes for male patients; P <0.05), with delayed treatment at all stages: median pain onset-to-call time, 60 vs. 44minutes (P <0.0001); call-to-door, 130 vs. 125minutes (P <0.05); and door-to-balloon (or thrombo-aspiration) in primary angioplasty, 45 vs. 40minutes (P <0.05). Thus, the median time from first medical contact to balloon inflation or thrombo-aspiration was 95minutes: 100minutes in female versus 94minutes in male patients (P <0.05), and<120minutes in 65% of female versus 72% of male patients (P <0.0001). Table 2 presents revascularization strategies according to gender, showing lower rates of use of the various reperfusion techniques in women.

Inhospital evolution

As seen in Table 3, inhospital morbidity and mortality were significantly higher in women, with higher rates of high-grade atrioventricular block and atrial fibrillation and lower left ventricular ejection fractions. Likewise, total hospital stay was longer. Above all, mortality from all causes was higher: 9% vs. 4% (P <0.0001). These deaths were mainly due to cardiovascular causes: 90% of deaths in female patients and 89% of deaths in male patients. Death from haemorrhage was rare (n =11); three male versus eight female patients (P <0.001), including eight intracranial haemorrhages (two male, six female; P =0.002) and one retroperitoneal haematoma (in a male patient). As seen in Table 4, which compares inhospital mortality by age and gender, excess mortality mainly affected female patients aged<60years, in the univariate analysis. Finally, the rate of haemorrhagic events of any severity, systematically screened in 427 patients, was 3% in female versus 2% in male patients (P =0.48).

Discharge treatment

Table 5 shows the rate of prescription of the various treatments recommended by the European Society of Cardiology [10] at discharge, according to gender, again showing underprescription for women in all cases.

Adjusted analysis of inhospital mortality

Female STEMI patients had a significantly higher unadjusted inhospital mortality than male patients with STEMI (model 1): HR 1.96, 95% CI 1.53–2.52; P <0.0001. This excess mortality persisted after adjustment for patient characteristics (model 2) (HR 1.36, 95% CI 1.04–1.79; P =0.02) and after adjustment for time to revascularization (model 3) (HR 1.37, 95% CI 1.05–1.80; P =0.02). Finally, ‘complete’ adjustment, for patient characteristics, time to revascularization and revascularization technique (model 4), gave an HR of 1.33 (95% CI 1.01–1.76; P =0.04), revealing excess female inhospital mortality in STEMI, independent of all study variables (Figure 1).



Figure 1


Figure 1. 

Unadjusted and adjusted hazard ratios for mortality in female patients with STEMI. Model 2: adjusted for age, diabetes, arterial hypertension, active smoking, anterior STEMI location, and three-vessel or common left main coronary disease. Model 3: adjusted for the variables in model 2 plus overall ischaemia time. Model 4: adjusted for the variables of model 3 plus coronary angiography, primary angioplasty, radial arterial approach, thrombo-aspiration, glycoprotein IIb/IIIa inhibitor administration, and fibrinolysis. CI: confidence interval; STEMI: ST-segment elevation myocardial infarction.

Zoom

Discussion

The present study highlights the specificities of STEMI and its prognosis in female patients: onset associated with higher co-morbidity rates; later and less-optimal treatment; and, above all, much poorer inhospital prognosis, especially in younger women.

The present female prevalence for STEMI (about one in four) is in full agreement with French national data [5, 11]. Likewise, the present rate of co-morbidity in female patients is in agreement with recent registry reports [2] – notably a higher mean age in females: 65.5 vs. 61.2years in an American registry [7]; 71 vs. 62years in the German MITRA registry [12]; and 67 vs. 56years in the Korean Acute Myocardial Infarction National Registry [3].

Time to revascularization

ORBI revealed significantly longer ischaemia times in women, due to lower rates of use of the SAMU emergency service, lower electrocardiographic input and longer delays to all types of treatment, as found in other registries [13, 14]. Thus, the median pain-to-door time was 195minutes for women versus 150minutes for men in the American registry [14] and 217minutes for women versus 161minutes for men in the Korean registry [3]. Most notable was the significantly longer (by 16minutes) pain-to-call time in the ORBI data, indicating a need for greater awareness of the issue of STEMI on the part of women and an early call for specialized help (SAMU) in case of chest pain, to allow direct admission to the catheterization laboratory [8, 10].

Management

The present study also found a very clear gender-related difference in coronary revascularization strategy. Here again, underutilization of fibrinolysis and angioplasty in female patients has frequently been reported [3, 4, 12, 14, 15]. Most registries, however, fail to specify revascularization techniques, and data on arterial approach or thrombo-aspiration, for example, are seldom reported. The present study found significant differences in these two aspects of revascularization, despite recommendations (European Society of Cardiology guideline: IIa [10]): although of proven benefit in terms of mortality [16], the radial approach is less often used in female patients (40% vs. 51%; P <0.0001). Likewise, despite proof of benefit [17], thrombo-aspiration is, again, less often used in women (46% vs. 55%; P <0.0001).

Prognosis

Poorer inhospital prognosis for female STEMI patients has been frequently reported [3, 4, 6, 7, 18, 19]. The main contribution of the present study lies in its analysis of this excess female mortality, with a two-fold greater rate of inhospital death in women.

Firstly, it emerged that the excess mortality exclusively concerned younger women, being significant only in those aged<60years, with a trend in those aged 60–70-years; in older female patients, no differential mortality was found. This age–gender interaction was also observed in the American registry [7], with post-STEMI inhospital mortality being 98% greater in 50-year-old women than in men of the same age, but identical in both sexes after 80years: 12.2% in female and 12.3% in male patients. This is an especially worrying factor, as a recent analysis of French STEMI data found that there has been a constant increase in the proportion of young women in the STEMI population over the last 15years: 11.8% of women were aged<60years in 1995 versus 25.5% in 2010 (P <0.001) [5].

Moreover, it emerged that this excess mortality was not simply due to greater co-morbidity (model 2), longer time to revascularization (model 3) or revascularization strategies that were less ‘aggressive’ and less in line with scientific recommendations (model 4). Rather, female gender, as such, emerged as a factor for elevated risk of inhospital mortality. Few registries have undertaken such an analysis of female inhospital mortality data that they hold. However, an analysis of the Korean data, using a methodology similar to the present study, showed that the excess female mortality that persisted after adjustment for age became non-significant when adjusted for age, medical history, haemodynamic status and ‘clinical performance’ [3]. A previous analysis of data from the New York State registry also showed significant excess mortality in women aged<75years, which disappeared after adjustment for age, co-morbidity and haemodynamic status [20]. Likewise, a recent report from a French registry also highlighted an impact of the age–gender interaction, but with higher hospital mortality in the subgroup of women aged>65years [21]. This single-centre registry studied 2600 patients (including 199 women aged<65years) in a 23-year period. Therefore, the impact of this age–gender interaction is different according to the inclusion period. One quality of our multicentre registry was the inclusion of a high number of patients in quite a short period, with homogenous STEMI support.

We have no clear explanation for this excess female mortality. It has been suggested that in STEMI, prehospital mortality is higher in male subjects [22], counterbalancing the excess female inhospital mortality. It is also established that young women benefit from hormonal protection against atherosclerosis [23]; it may thus be the case that premenopausal women admitted for STEMI are those with especially severe atherosclerosis or in whom risk factors have accumulated. Moreover, as young women show less stenosis in the coronary network than men, they develop a lower ischaemic myocardial protection response, resulting in greater vulnerability to acute ischaemia [24]. Finally, the mechanism of coronary occlusion may vary according to age, with plaque erosion predominating in younger subjects and rupture in those aged>50years [25].

Study limitations

As ORBI is specifically a French registry, the present findings may not be extrapolated elsewhere. Moreover, ORBI is, by definition, restricted to patients admitted to an interventional cardiology centre, which may induce selection bias: STEMI cases managed medically in a non-interventional setting are not included. It is, however, unlikely that women and men from the same age group are referred differently.

Conclusion

The present analysis of ORBI registry data found that about one-quarter of patients admitted for STEMI were female, with a significantly greater rate of co-morbidity than in men. Moreover, time to revascularization was significantly longer, partly due to women delaying their call for medical help, and treatment strategies were less-optimal, both in the acute-phase and at discharge. Women, and especially younger women, thus show excess inhospital mortality that is only partly accounted for by the above factors and which persists after adjustment. It would therefore seem necessary to raise awareness of the issue, among the female population in particular, but also among emergency staff and cardiologists. Only management that is at least as ‘optimal’ for women as for men can reduce this mortality rate.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.


Acknowledgments

We would like to thank the team of clinical research assistants who ensured data collection: E. Babin and A. Piel (CHU de Rennes); P. Héry (Clinique Saint-Laurent, Rennes); F. Langlais (Centre Hospitalier de Saint-Brieuc); P. Dias and C. Kergoulay (CHU de Brest); and P. Rameau and M. Paquin (Centre Hospitalier de Quimper). We would also like to thank all the cardiologists and emergency and SAMU staff who collated the data.


Appendix A

The following medical centres participated in this study: CHU de Rennes; Clinique Saint-Laurent, Rennes; Centre Hospitalier de Saint-Malo; Centre Hospitalier de Saint-Brieuc; Centre Hospitalier de Lorient; Centre Hospitalier de Vannes; CHU de Brest; Centre Hospitalier de Quimper; Clinique du Grand Large, Brest.

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