Coronary heart disease (CHD) is a leading cause of death for women worldwide.1 Each year more women than men die from cardiovascular disease, most from myocardial infarction and sudden death.2 Owing to improvements in cardiac care, more women are living with CHD than ever before.3 In patients with an acute coronary syndrome (ACS), understanding possible sex differences related to symptom presentation, management and outcomes will assist in advancing current management of ACS in women.

Several studies have reported differences in the clinical presentation and baseline comorbidities of men and women with ACS.4^–7 Women are typically older and more likely to have hypertension, diabetes and metabolic syndrome but are less likely to smoke tobacco than men.8^–10 Women with ACS are less likely than men to undergo cardiac catheterisation and subsequent revascularisation procedures9 11 12 or to receive glycoprotein IIb/IIIa inhibitors while in hospital or to be discharged on evidenced-based cardiac therapies.5 9 10 13 14 Women with ACS have worse in-hospital and long-term prognoses than men in some,15^–18 but not all studies.9 10 Many of these studies were completed over a decade earlier; in the meantime treatment strategies for patients with ACS have evolved. Furthermore, data from previous studies are often from randomised trials or specialised populations such as women referred for angiography. Data on a diverse, multiethnic population of real-world patients admitted for ACS, which includes large numbers of women, are scarce. The Global Registry of Acute Coronary Events (GRACE) is a unique dataset with extensive information on ACS presentation characteristics, angiographic data, management and outcomes, which includes large numbers of both men and women patients admitted for ACS.

Using data from GRACE, a large, multinational, observational study, we investigated whether women presenting with ACS have different symptoms, severity of obstructive angiographic coronary artery disease (CAD) and six-month outcomes compared to men. In addition, we examined the use of medical and interventional therapies in women and men to determine if differences in interventional therapy were the result of pathophysiological disparities in disease.

METHODS

Full details of the GRACE methods have been published.19^–21 GRACE is designed to reflect an unbiased population of patients with ACS, irrespective of geographic region. A total of 113 hospitals located in 14 countries (Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, New Zealand, Poland, Spain, the United Kingdom and the United States) have contributed data to this observational study. Patients from 93 hospitals were included in this analysis.

Adult patients (⩾18 years old) admitted with a presumptive diagnosis of ACS at participating hospitals were potentially eligible for this study. Eligibility criteria were a clinical history of ACS accompanied by at least one of the following: electrocardiographic changes consistent with ACS, serial increases in biochemical markers of cardiac necrosis (creatine kinase isoenzyme, creatine phosphokinase or troponin) and documented coronary artery disease. Patients with non-cardiovascular causes for ACS, such as trauma, surgery or aortic aneurism, were excluded. Patients were followed up at approximately six months by telephone, clinic visits or through calls to their primary care physician to ascertain the occurrence of several long-term outcomes. Where required, study investigators received approval from their local hospital ethics committee or institutional review board.

To enrol an unselected population of patients with ACS, sites were encouraged to recruit the first 10–20 consecutive eligible patients each month. Regular audits were performed at all participating hospitals. Data were collected by trained study coordinators using standardised case report forms. Demographic characteristics, medical history, presenting symptoms, duration of pre-hospital delay, biochemical and electrocardiographic findings, treatment practices and a variety of hospital outcome data were collected. Standardised definitions of all patient-related variables, clinical diagnoses and hospital complications and outcomes were used. All cases were assigned to one of the following categories: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina.

Patients were diagnosed with STEMI when they had new or presumed new ST-segment elevation ⩾1 mm seen in any location or new left bundle branch block on the index or subsequent ECG with at least one positive cardiac biochemical marker of necrosis (including troponin measurements, whether qualitative or quantitative). In cases of NSTEMI, at least one positive cardiac biochemical marker of necrosis without new ST-segment elevation seen on the index or subsequent ECG had to be present. Unstable angina was diagnosed when serum biochemical markers indicative of myocardial necrosis in each hospital’s laboratory were within the normal range. Full definitions can be found on the GRACE website at www.outcomes.org/grace. Hospital-specific feedback regarding patient characteristics, presentation, management and outcomes was provided to each centre on a quarterly basis in the form of written reports.

Angiographic data were analysed by physicians at the enrolling GRACE hospitals. Patients were considered to have advanced disease if any epicardial vessel had ⩾50% stenosis. The extent of CAD was further categorised as having one-vessel, two-vessel or three-vessel disease, depending on the number of vessels affected. Normal or mild disease was defined as stenosis <50% in any of their major epicardial vessels. Patients were stratified by sex and severity of angiographic disease: normal or mild disease vs advanced disease.

Data analysis

Comparisons of baseline characteristics, treatment practices, clinical outcomes and angiographic data between men and women with normal and mild disease and advanced disease were examined using the χ² tests for categorical variables and Kruskal-Wallis tests for differences in continuous variables. All tests were two-sided and considered significant at α⩽0.05.

To assess whether there was a sex-based difference for interventional therapy, or if treatment was matched to a different disease process in women, we examined rates of revascularisation in hospital among men and women with normal or mild disease on angiograms and those with advanced disease. We examined all baseline characteristics for factors associated with receipt of cardiac catheterisation by sex. We compared use of in-hospital medications according to sex and disease severity. We examined differences in six-month post-discharge outcomes of death, myocardial infarction, stroke, rehospitalisation and the combined end point (death, myocardial infarction, stroke and rehospitalisation) in men and women according to their disease severity. After excluding patients who died in hospital, the follow-up rate at six months after hospital discharge was 80% (80% for men; 79% for women) for the 26 755 patients included in this study. Logistic regression analysis was used to adjust for age differences between men and women with varying degrees of coronary artery disease in addition to hospital cluster, receipt of cardiac catheterisation, ACS type, past or current smoking, positive cardiac biomarkers, transfer into a GRACE hospital and history of hypertension, angina, congestive heart failure, diabetes mellitus, myocardial infarction, stroke, percutaneous coronary intervention, or coronary artery bypass graft surgery. Interaction terms were included in the models to assess whether sex differences in outcomes by receipt of catheterisation and ACS type existed.

RESULTS

Baseline characteristics

Of the 57 406 consecutive patients enrolled in GRACE between April 1999 and March 2006, 9574 were excluded owing to missing data and 4439 were excluded because they were not diagnosed with ACS at discharge. For the present study, subjects were included if they had a discharge diagnosis of ACS (n = 43 393), of which 16 638 (10 096 men and 6542 women) did not receive coronary angiography; 26 755 (19 117 men and 7638 women) received coronary angiography and constitute our study group.

Women were, on average, older than the men in both the groups who received coronary angiography and in the group that did not (table 1). Most patients had at least one cardiovascular risk factor. Among those who had a cardiac catheterisation, women had higher rates of prior angina, heart failure, diabetes and hypertension, but were less likely to smoke. Women were less likely to have a history of myocardial infarction but were more likely to have a history of transient ischaemic attack or stroke. In terms of past interventions, women were less likely to have had a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). On presentation, men and women had similar rates of positive cardiac biomarkers but women were less likely to have STEMI. Similar trends were seen among those who did not receive a coronary angiography with the exception of a history of angina, which was similar in men and women.

Symptom presentation and angiographic classification

Among patients with documented myocardial infarction in whom symptom data were collected, chest pain was the most common symptom for both men (94%) and women (92%). Among those without chest pain, women were more likely to present with atypical symptoms including jaw pain and nausea or vomiting (table 2).

We then examined factors associated with receipt of cardiac catheterisation. Male sex, age, past or current smoking, positive initial cardiac biomarkers, transfer into a GRACE hospital, and a history of hypertension or percutaneous coronary intervention were positively associated with receipt of cardiac catheterisation, while a history of angina, congestive heart failure, myocardial infarction, and stroke were negatively associated with receipt of cardiac catheterisation. Women were twice as likely to have normal vessels or mild disease as men (12% vs 6%) and were less likely to have left-main and three-vessel disease (27% vs 32%, p<0.001, table 3).

Medical and interventional therapy

Particularly for mild disease, men were more likely to get PCI than women (17% vs 7%, p <0.001, table 4). Rates of CABG were approximately the same.

Men and women with mild disease were less likely to receive β-blockers, statins and angiotensin-converting enzyme (ACE) inhibitors than those with advanced coronary disease, with women having the lowest rates for receipt of these medications. Both women with mild disease and women with advanced disease were less likely to receive β-blockers and/or statins compared with men with similar disease severity (table 5).

Clinical outcomes

In-hospital death rates were 2.6% (496/19 078) for men and 4.5% (339/7613) for women. At six months, men and women with normal or mild disease had similar rates of the composite end point (death, myocardial infarction, stroke or rehospitalisation). Among patients with advanced CAD, women had a higher rate of the combined end point compared with men (25% vs 20%, p<0.001, table 6). These differences remained after adjustment for age and number of diseased vessels (odds ratio (OR) 1.25; 95% confidence interval (CI) 1.14 to 1.34); however, differences in death rates between men and women were similar after adjustment for age and number of diseased vessels (OR 0.97; 95% CI 0.81 to 1.15) (appendix). For one-vessel, two-vessel or three-vessel disease, women were consistently more likely to be rehospitalised than men. For the subset of patients with mild CAD or normal coronaries, no sex differences were observed with regard to rehospitalisation. We also examined the data for possible interactions by receipt of catheterisation. Outcomes were similar for both men and women for death, myocardial infarction and stroke, irrespective of receipt of coronary angiography. For rehospitalisation, women who had had a cardiac catheterisation were more likely to be rehospitalised at six months compared to men who had had a cardiac catheterisation (odds ratio 1.21, 95% confidence interval 1.11 to 1.33), while there were no such differences among men and women who did not have a cardiac catheterisation (odds ratio 1.00, 95% confidence interval 0.91 to 1.11). We also examined the data according to ACS type and again found a similar result, with no significant differences among men and women for death, myocardial infarction and stroke; however, women with either STEMI or NSTEMI were more likely to be rehospitalised compared to men with STEMI or NSTEMI (odds ratio 1.14, 95% confidence interval 1.02 to 1.28 and 1.22, 1.09 to 1.36, respectively). No such differences were observed for unstable angina.

DISCUSSION

In this large cohort of men and women admitted for ACS, we observed sex differences in atypical symptoms, extent of angiographic disease, management and six-month outcomes among those who underwent cardiac catheterisation.

Presenting symptoms

In our study, most patients—including women—presented with chest pain. Previous studies suggest that typical symptoms such as chest pain are as sensitive a marker for ACS in women as they are in men.7 However, many women with ACS do not report a history of chest pain or angina.22^–24 In our cohort, the numbers of women and men with a history of angina were similar. There is evidence to suggest that older women present with similar symptoms to men, including typical angina.25 Data from the Worcester Heart Attack Study observed no sex differences in chest pain symptoms for those aged 65–74 years, but lower rates of chest pain for women vs men after the age of 75 and lower rates in younger women (less than 65 years).23 The age of women in our cohort (median 65 years) may explain the similar rates of chest pain (for men and women). Among those presenting without chest pain, women were more likely to report jaw pain or nausea compared with men. Similar observations have been noted in other cohorts. One study using the Acute Coronary Syndrome Registry from the University of Michigan examined presenting symptoms of patients with ACS.26 The authors reported that women were more likely to present with nausea compared with men. As in our study, the numbers of patients with presenting symptoms of chest pain or dyspnoea did not differ by sex.

Review of angiographic data

With regard to the extent of atherosclerosis found at catheterisation, we observed that women were twice as likely to have normal vessels or mild disease and were less likely to have three-vessel or left-main disease as men. These results are similar to the angiographic data from many clinical trials and registries that have reported less angiographically significant obstructive CAD and multivessel disease among women than men.27^–32 Hochman et al27 showed that one in four women who met strict criteria for angina at rest and electrocardiographic changes or previous documented disease had no significant obstructive coronary disease on cardiac catheterisation. The Women’s Ischemia Syndrome Evaluation (WISE) study observed that women referred for angiography had a lower likelihood of obstructive CHD than anticipated from angiography studies in men.33 34

Treatment differences

Although women were more likely to have mild disease on angiography, rates of positive cardiac markers were similar for both sexes. In our study, with the exception of aspirin, fewer women with mild disease received β-blockers, statins or ACE inhibitors than women (or men) with extensive CAD or men with mild disease. Women with more extensive disease were also less likely to receive beneficial medications compared with men. Data from previous studies demonstrated a similar pattern.35 36 Vaccarino et al, using data from the National Registry of Myocardial Infarction (NRMI), observed lower rates of use of aspirin and β-blockers for women, with black women having the lowest rates.37 As in our findings, these sex differences were small, yet statistically significant, and parallel an observed increased risk for adverse outcomes for women compared with men. The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) study noted reduced rates of statin use for women vs men at time of discharge.36 In a recent study examining trends in secondary prevention in the United Kingdom, women were less likely to receive statins, β-blockers and ACE inhibitors compared to men; however, these were predominately explained by several factors including disease severity, age and lack of comorbidities.38 In our population, rates of statin use were particularly low among women with mild disease despite the presence of cardiac risk factors and the relatively high rate of positive cardiac biomarkers. Thus statin therapy at discharge represents an important opportunity for quality improvement, particularly in women with mild disease.

Women in our cohort with mild disease were less likely to undergo PCI than men. Rates of CABG and PCI among patients with advanced disease were similar. Data from the Myocardial Infarction Triage and Intervention (MITI) registry observed larger sex differences.39 Women in the MITI cohort received coronary angiography, PCI, thrombolysis or CABG at half the rate of the men, despite all subjects having confirmed acute myocardial infarction. Several other studies have shown similar differences in use of angiography,17 35 PCI5 14 40 and acute reperfusion therapy (PCI or thrombolytic drugs).9 10 37 Vaccarino et al, using data from NRMI, examined treatment practices among patients with acute myocardial infarction between 1994 and 2002.37 These sex differences in treatment persisted over time. Women, black women in particular, were less likely to receive reperfusion therapy compared with white men. Recent simulation data support the concept that while there is underuse of PCI in women compared to men with acute myocardial infarction, a broader use of PCI would be associated with improved outcomes, although the protective effect of PCI is somewhat less in women than in men.41

Six-month outcomes

Among men and women with normal or mild disease, we observed no differences in clinical outcomes at six months. Rates of end points such as death, myocardial infarction and stroke were low in this group. In a two-year follow-up of patients with suspected ischaemia from the WISE study, Sharaf et al demonstrated that almost 10% of women with minimal angiographic disease died or had a myocardial infarction.42 The present study had six-month follow-up data; perhaps had longer-term follow-up data been available, we may have observed cardiac event rates similar to the above findings. Other studies have observed increased cardiovascular disease event rates among those with non-obstructive coronary disease by cardiac angiography. A retrospective analysis of pooled dated from three of the Thrombolysis In Myocardial Infarction (TIMI) trials (TIMI 11B, TIMI 16 and TIMI 22) examined patients with non-obstructive coronary artery disease (normal or <50% stenosis).43 Of the 710 patients with non-obstructive coronary artery disease, 48% had normal coronaries and 51% had mild disease. During one-year follow-up, 2% of these patients had a myocardial infarction or died. Sex differences were not examined in that study; however, these data identify the need for risk-factor modification in patients with non-obstructive disease to include those with normal coronaries by angiography.

Strengths and limitations

GRACE is the largest multinational registry to include the spectrum of patients with ACS. “Real-life” studies such as GRACE offer the advantage that they provide data on a heterogeneous patient population that includes groups who are often under-represented in randomised trials. Nevertheless, as a non-randomised observational study, GRACE is subject to certain inherent limitations and potential biases. Since the treatment and follow-up data in this study are limited to patients who underwent coronary catheterisation, the generalisability of these findings to all patients with ACS is not possible. Angiographic interpretation was based on the semi-quantitative clinical report, not on the results of a blinded core laboratories and/or quantitative coronary angiography interpretation. Categorisation of lesions >50% stenosis as advanced CAD is likely to include patients whose degree of stenosis is fairly mild; however, data abstraction forms limit information regarding CAD stenosis. Based on our conservative approach, it is likely that sex-related outcomes may in fact be more significant among patients with stenosis >70%.

CONCLUSIONS

Several studies have shown differences in the presentation, treatment plans and outcomes for men and women with ACS.1 15^–18,44^–47 Many questions remain regarding the relation between sex and development of CAD, symptoms presentation and treatment differences. Our study was one of the largest cohorts of men and women who comprise a multiethnic group of patients with an ACS. We observed that women presenting with an ACS were more likely to have minimal CAD, which may partially account for different treatment choices compared with men. However, women were more likely to have comorbidities such as hypertension and diabetes mellitus; thus, further understanding of these management differences, in particular use of cardiac medications such as statins, is warranted. In addition, further research regarding possible sex difference in disease severity will assist us in the prevention of ACS as well as in its management. These findings suggest that our understanding of ACS in women is far from complete.