Historically, coronary artery disease (CAD) has been perceived as a disease of men, rarely presenting in women, which leads to under-appreciation by health professionals of symptoms in women.1 However, this historical view is no longer correct, since CAD is now becoming the leading cause of death in women in Western society, overtaking uterine cancer, breast cancer and peripartum mortality.2 In Europe, around 23% of all deaths in females are due to CAD, and, although the number of women diagnosed with CAD has grown substantially in the last few years compared to men, the disease is still clearly underdiagnosed and undertreated in women, who have less access to revascularization and optimal medical therapy.2 In addition, although in recent decades there has been a significant reduction in mortality from myocardial infarction (MI), mainly in those aged over 65 years, there is evidence that this improvement in incidence and mortality is slowing down, especially in younger women aged under 55 years.3

The main objective of this work is to assess the approach to acute coronary syndrome (ACS) in Portugal, including form of presentation, in-hospital treatment and in-hospital complications, according to gender and in three different time periods: 2002-2010, 2011-2015, and 2016-2019, using data from the Portuguese Registry on Acute Coronary Syndromes (ProACS) of the Portuguese Society of Cardiology and the National Center for Data Collection in Cardiology.

We performed an observational study with retrospective analysis of all patients included in the ProACS between 2002 and May 15, 2019 (n=49 247).

Cardiovascular disease (CVD) is the leading cause of death in both sexes worldwide. Each year, according to the 2017 European Cardiovascular Disease Statistics, CVD is responsible for 3.9 million deaths in Europe, accounting for 45% of all deaths, and is the leading cause of death in women in all except two countries. The largest gap in mortality by gender is found in the Baltic states, Slovenia and Romania, where the percentage of women dying from cardiovascular diseases is 13.5-17.4% higher than in men.6 Another European analysis from 2015 shows that the difference between the sexes is more marked regarding ischemic heart disease (IHD); however, unlike in all CVD, the mortality rate from IHD is 1.8 times higher in men.7 Our results show that in Portugal, although published data from the ProACS indicate that in-hospital mortality has declined steadily since 2002,8 in the period studied, among patients admitted to hospital with ACS women were more likely to die than men. This apparent difference in results may be due to the fact that official European data analyze overall mortality from IHD (which includes a spectrum of disease) over time, unlike our work, in which we assessed a single event in the continuum of IHD and associated in-hospital mortality. However, it should be borne in mind that this higher mortality is unadjusted for other variables, and in a report from China, in which unadjusted in-hospital mortality for women initially appeared to be higher, this was no longer the case after adjustment for clinical characteristics and acute treatments.9 A similar result was seen in a study on patients from the ProACS, in which after propensity score adjustment, gender was no longer a predictor of in-hospital mortality.2

When traditional cardiovascular risk factors were analyzed, there was a higher prevalence of hypertension, dyslipidemia, diabetes and obesity and a growing prevalence in the periods studied of smoking, diabetes and dyslipidemia in women, showing that the efforts of the health community to call attention to the need for better risk factor control are still insufficient, since despite the growing number of patients at hospital admission who are, for example, prescribed antihypertensive and statin therapy, these patients are still lower in number than those diagnosed with ACS à despite the growing number of patients that at hospital admission are, for example, treated with anti-hypertensive therapy and statins; those are still in lower number than those with the diagnosis.

Data from the US Centers for Disease Control and Prevention show that women are less likely to be prescribed a statin, and that their therapeutic adherence is also low.10,11 In terms of secondary prevention, a meta-analysis performed by the Cholesterol Treatment Trialists’ Collaboration with 170 000 patients from statin trials shows that a reduction of 38.66mg/dl in LDL cholesterol is associated with a 22% relative risk reduction in major vascular events, the results being similar for both sexes.12 Despite this evidence, in our study women were undertreated with statins both during hospitalization and at discharge, even though the prevalence of dyslipidemia is higher in women. It is unclear whether this is due to a higher prevalence of adverse effects of statins in women than in men, but it probably signals the need for greater physician and patient awareness.

Hypertension is more strongly associated with MI in women than in men.13 Furthermore, pregnancy-related complications such as pre-eclampsia and gestational hypertension are associated with a greater long-term risk of developing hypertension and CVD, and postmenopausal women are also more likely to have a non-dipper pattern, which has been associated with worse cardiovascular outcomes and target organ damage.14,15 There is no evidence that antihypertensive therapy has a different efficacy or safety profile in women, even though most trials do not analyze their data by gender. In our study, we found no differences in the prescription of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) between genders, either during hospitalization or at discharge, but the rate of beta-blocker prescription was higher in men at both times. The prescription of other antihypertensive therapy during hospitalization or at discharge is unknown.

Compared to women without diabetes, those with diabetes have a three-fold higher risk of fatal CAD, and their risk is also higher than in men with diabetes. Women with diabetes have a more aggressive profile of CAD, related to greater impairment of endothelium-dependent vasodilation and greater likelihood of hypercoagulable states, atherogenic dyslipidemia, and metabolic syndrome. Considering that the harmful effects of glucose begin to occur at blood glucose levels lower than those currently accepted for a diagnosis of diabetes, the transition from normoglycemia to glucose intolerance and diabetes may be more detrimental in women.16–18 Although there was no difference in the rate of prescription of insulin or oral antidiabetic therapy between the sexes before hospital admission, during hospitalization and at hospital discharge there were significant differences, combined with the underdiagnosis of diabetes in outpatients and/or undertreatment.

Smoking is the most important preventable cause of MI in women, and a major risk factor for women aged <55 years, leading to an increase in the risk of MI. Although there has been an overall reduction in the use of tobacco products in the US, this decline is considerably less marked in women,19,20 which agrees with our data.

The prevalence of obesity is higher in women, as well as the impact that this risk factor has on the development of CAD. In the Framingham Heart Study, obesity increased the relative risk of CAD by 64% for women (vs. 46% for men). Despite this knowledge, the prevalence of obesity in women with ACS is still higher than in men.21 Additionally, women have other non-traditional risk factors that are not analyzed in our study, such as depression, premature labor, radiotherapy for breast cancer, and many chemotherapy drugs.

It is increasingly recognized that CAD in women is not restricted to obstructive atherosclerotic coronary disease, but also includes microvascular and endothelial dysfunction, coronary vasomotor abnormalities, and spontaneous coronary artery dissection. This extended spectrum of a single disease creates difficulties not only in diagnosis but also in treatment, resulting in women frequently being underdiagnosed and undertreated if they do not present with the typical pattern of obstructive coronary atherosclerosis.22 This is a possible explanation for our finding of a significant difference between the sexes regarding coronary angiograms with normal coronary arteries or with <50% stenosis, which reflects a well-known paradox: women had a higher prevalence than men of stable angina pre-hospital admission (29.1% vs. 23.8%, p<0.001) and less likelihood of obstructive CAD on coronary angiography (5.7% vs. 11.7%, p<0.001) but a worse prognosis (in-hospital mortality 6.9% vs. 3.7%, p<0.001). In addition to this, pathology and image studies have shown that women have smaller coronary arteries, a more diffuse pattern of atherosclerosis with fewer obstructive lesions, and a greater incidence of plaque erosion as the substrate of acute thrombosis.23 This paradox of less obstructive CAD with worse outcomes can, at least in part, be explained by the connection between microvascular disease and coronary atherosclerosis; in addition, there is increasing evidence that more extensive non-obstructive CAD is associated with a similar rate of adverse cardiovascular outcomes to obstructive CAD.24

With regard to clinical presentation of ACS, our results confirm what was previously known: women more frequently have atypical symptoms, even though the most common presenting symptom is still chest pain.25,26 This gender difference in clinical presentation affects the timely identification of ischemic symptoms, appropriate triage, and therapeutic approach, leading to delays in revascularization and higher mortality. In a study in France, all the timings were longer in women; in-hospital morbidity and mortality rates were also significantly higher, and rates of prescription of guideline-recommended therapies were lower.27 Our results are in line with these findings and those of similar studies, and all the timings analyzed were longer in women, regardless of whether the starting point was symptom onset, FMC or arrival at the door. However, comparing the two more recent periods, FMC-to-needle, door-to-needle and symptom onset-to-balloon times improved in women, unlike in men, and in both sexes there were improvements in FMC-to-balloon, door-to-wire crossing, door-to-balloon, and FMC-to-wire crossing times. On the other hand, in these two more recent periods, longer times were observed in women from symptom onset to admission, wire crossing and needle, as well as from FMC to admission, leading to the conclusion that overall, although after FMC and/or hospital admission the path to treatment is becoming more efficient, the female population do not seem to be aware of the need for timely recognition of the signs and symptoms of MI, leading to greater delays, particularly in patient-dependent times. A similar discrepancy has been observed in other countries, including New Zealand, Australia, France and the USA.27–29 Another important point is the paradoxically greater delays in STEMI quality indices when the period 2002-2010 is compared to the two more recent periods. The mortality benefit achieved with primary PCI in STEMI patients is reduced by treatment delays,30 and mortality fell between these periods.8 This paradox was addressed in a Portuguese study from 2017,8 in which the authors state that, while there have been improvements in centers with a catheterization laboratory, with the proportion of patients with door-to-balloon time <60min rising from 52.5% to 73.5% (86.1% <90min), in centers without PCI facilities, the timings vary widely over the years, and were <60min in only 14.6%, <90min in 22.4% and <120min in 36.5%. In addition, there was considerable variability in the first years of the registry in centers without PCI facilities, associated with the smaller number of patients in these groups. This variability in the first years of the registry and the differences between centers with and without PCI facilities may be partly responsible for the paradox.

The high risk profile of women undergoing primary angioplasty, in terms of both ischemic risk (as shown by the GRACE score) and bleeding risk (as shown by the CRUSADE score), is reflected in a higher proportion of no or non-significant coronary lesions in our study, less extensive CAD and a lower prevalence of multivessel disease on coronary angiography in women compared with men. These findings are similar to those of a previous study in which the authors showed that despite the higher risk profile of women, there were no differences between the sexes in the extent of coronary disease or the prevalence of multivessel disease.2 It should be borne in mind, however, that this risk profile is essentially a clinical assumption, considering that in ACS little is known regarding the prognostic factors for adverse outcomes in women, and, although several risk scores such as GRACE and TIMI are commonly used, these were developed based on populations of which two-thirds were male, and so their performance in women is not well established.22

Despite the clear recommendation in the guidelines for radial access as the preferred mode of access, and the higher bleeding risk of women, our data indicate that this arterial route is less used in women, even though a substudy of the MATRIX trial showed that women have greater risk of severe bleeding and access complications, and that radial access is an effective way of reducing these complications.31

Even after adjusting for factors like age, comorbidities and disease severity, several studies have shown that women are less likely to be given recommended therapies either at hospital admission or at hospital discharge, including beta-blockers, ACEIs/ARBs, and statins.27,32,33 Our results indicate that for ACEIs/ARBs the prescription rate is similar to men (unlike statins and beta-blockers), which itself may represent under-prescription, considering the higher risk profile of women, as demonstrated by the fact that women have more complications, such as sustained VT or the need for non-invasive ventilation, even though they have less extensive CAD.34 Factors that may contribute to this finding in women are their higher rates of diabetes, hypertension, and obesity, a higher prevalence of outpatient HF, delays between symptom onset and reperfusion therapy, a higher prevalence of acute kidney injury, and the fact that they may less frequently be offered reperfusion therapy and medication for secondary prevention.

The observational nature of this study means that we cannot exclude the existence of possible additional confounders that are not identified or accounted for in the data analysis. Furthermore, although the data from ProACS is largely representative of the various geographic regions of Portugal, it is not possible to infer conclusions about the country as a whole. As the registry is voluntary, it is not possible to ensure that patients were included consecutively; some ACS patients were not hospitalized in cardiology departments and therefore are not included in the database; and only patients who were admitted alive are included, and so a proportion of patients with fatal complications before admission were omitted from the analysis. In addition, the number of records has decreased in recent years, which may have led to bias when comparing periods, and as the registry is voluntary, some data may have been missed, leading to data inconsistencies. Another limitation of our study is that some data were only collected after October 2010, and so a considerable number of patients did not have all of their parameters recorded.

The number of women with CAD is increasing; however, compared with men, this disease is still underdiagnosed and undertreated, and women have less access to revascularization and optimal medical therapy. Although in the overall population a significant increase in the use of PCI was observed, there is still a statistically significant difference in its use between the sexes; women are less likely to receive guideline-recommended therapy in the context of secondary prevention, even in the most recent time period; and in-hospital complications and unadjusted mortality are still higher in women, despite improvements in overall mortality over the years. These findings are based on a voluntary registry and the inherent limitations should be borne in mind.

Greater awareness of both patients and health professionals is urgently needed to change the way ACS is treated in women.

The authors have no conflicts of interest to declare.