Gender Differences in Treatment and Outcomes of Patients with Acute Coronary Syndromes

Coronary Artery Disease (CAD) has been considered for many years a men’s disease. According to recent data, it actually represents the leading cause of death among women in the industrialized countries. The number of females among patients presenting with Acute Coronary Syndrome (ACS) is rising. Studies have shown significant gender difference in the presentation, treatment and outcome of patients with ACS [1-3]. Some investigators have reported that women with ACS are diagnosed later than men and receive less invasive cardiac procedures [1]. It has also been reported that women tend to decline certain diagnostic and therapeutic options [4], as well as that physicians are biased when treating in regard to current guidelines [5]. The general perception is that ARTICLE INFO ABSTRACT

women are at lower risk for coronary heart disease. This may have negative impact on the care of high risk women.The Czech Republic experiences one of the highest rates of coronary heart disease in women in Europe [6]. Thanks to the success of national randomized trials in acute myocardial infarction-the PRAGUE, PRAGUE-2 [7] the nationwide reperfusion network for patients with ACS has been established and early referral of ACS patients for invasive treatment has become a routine in the whole country. The number of primary PCIs performed for STEMI (657 per million populations in 2007) may even be the highest in Europe. In 2005 The Czech Society of Cardiology organized one-month prospective registry of acute coronary syndromes to assess the efficiency of the Czech hospital network in acute coronary care, to assess implementation of the new guidelines for the treatment of STEMI and NON-STEMI in daily practice and to analyze the incidence and outcomes of acute coronary syndromes in the Czech population. Results of this registry have been published recently [8]. The aim of the present analysis is to assess the impact of the national reperfusion network on the use of diagnostic procedures, therapeutic strategies and outcomes in Czech women.

Methods
An analysis of data from the CZECH (Czech evaluation of acute coronary syndromes in hospitalized patients) registry was performed. The details of the registry were reported in prior publication [8]. This registry collected data in two arms. The first arm "The regional registry» included all hospitals (n=17) in two Czech counties with a total population of 1 053 267 inhabitants.
The second arm "The PCI centers registry» included all 21 Czech PCI centers serving to the mean number of 488 095 inhabitants.

Patients
The entry criterion to this registry was hospital admission for

Data Collection and Analysis
Data of each patient were entered into a specifically designed 168-item case report form. The data were finally transferred into a central database, which was the basis for the specific information provided here. The Major Adverse Cardiac Events (MACE) -the death, re-infarction, stroke, heart failure, target vessel revascularisation and malignant arrhythmias were evaluated.
Baseline characteristics, medical and coronary interventions, and clinical outcomes were compared between women and men. For comparisons of continuous variables, linear regression was used, and for comparisons of categorical values, logistic regression was used. Comparisons between women and men were adjusted for differences in baseline factors, which influence clinical outcomes including age, diabetes and history of cardiovascular disease.
Logistic regression models were used for crude as well as adjusted analyses of in-hospital mortality. Multivariable models were constructed to determine the predictive value of gender on clinical outcomes. Of the 1345 patients with confirmed ACS, 1309 patients with complete data could be used for the analysis.The incidence was calculated only from the "regional arm" of this registry due to the fact, that this arm was organized to cover 100% of hospitalized patients (all existing hospitals) in a region with well-defined population.

Results
At discharge, the diagnosis of ACS was less frequently confirmed among women in comparison to men 62.3% vs. 75.4%, (p<0.001) in the whole studied group. In the regional registry the ACS was confirmed in only 43.2% of women vs. 57.4% of men (p=0.006).
In the PCI centers registry only 35.6% of enrolled patients with ACS were women, while in regional registry there were 43.7% of women. Among the patients with confirmed ACS the diagnosis of STEMI, NSTEMI and UAP was similarly frequent in women and men 28.2% vs. 32.9%, 39.0% vs. 36.4% and 32.8% vs. 30.7% (p=0.2) respectively ( Table 1). Incidence of acute coronary syndromes in women: The calculated annual incidence of hospitalized confirmed ACS (STEMI, NSTEMI or UAP) in women was slightly lower compared to men, 1419 vs. 1828 patients per million inhabitants.
The annual incidence of hospitalized, confirmed acute myocardial infarction (i.e., any type of infarction, without UAP patients) was 857 in women compared to 1103 in men per million inhabitants; the annual incidence of STEMI was 289 in women and 372 in men per million inhabitants. sion, no differences in the use of aspirin, statins, angiotensin-converting enzyme inhibitors, or beta-blockers between women and men were observed, although women were more likely to be treated with diuretics, dioxin, angiotensin I blockers, oral antidiabetics and with insulin ( Table 4). During the initial hospitalization, the use of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitor medications increased significantly among all patients. On discharge, the only significant difference in medication was the higher prescription rates of statins and clopidogrel in men (Table 5). Note: Data are expressed as mean or percentage (95% confidence interval). CABG = coronary artery bypass grafting; CVA= stroke; PCI = coronary angioplasty; MI = myocardial infarction. Note: Data are expressed in mmol/l as mean (95% confidence interval). Note: Data are expressed as mean or percentage (95% confidence interval).  (Table 6). Among patients treated with PCI the in-hospital mortality of women was 5.3% compared to 3.2% mortality of men (p=0.134); women had higher incidence of in-hospital acute heart failure (13.9% vs 9.2%, p=0.041). The incidence of other major adverse cardiac events (re-infarction, stroke, target vessel revascularization, serious arrhythmias) was similar in women and men treated with PCI, ( Table 8). Mortality of women treated with CABG was 3.9% compared to 2.9% mortality of men (p=0.9), ( Table 9). Mortality of women treated with any revascularisation was 5.2% compared to 3.0% mortality of men (p=0.086). Mortality of women treated conservatively (with medical treatment) was 6.6% compared to 16.3% mortality of men (p<0,001), (Table 10). In the multivariate analysis gender was not found to be an independent risk factor for MACE when adjusted for baseline variables (Table 11). Even, if the presence or absence of significant stenosis after angiography was also included in the statistical model, female gender was not found to be an independent risk factor for death or MI.

Discussion
Incidence: As in other population-based studies in the CZECH registry we have observed the higher incidence of an acute coronary syndrome among men compared to women. But the difference is small confirming the increasing number of women with ACS. We demonstrate that among patients who present with symptoms suggestive of cardiac ischemia, ACS is confirmed more often in men than in women. Some randomized studies, reported lower proportion of women among patients who had STEMI, compared to patients with other acute ischemic syndromes [9][10][11][12]. Among patients with myocardial infarction women presented more often with NSTEMI. Furthermore in some studies the ratio of men to women with a NSTEMI was significantly greater than in patients with unstable angina [10]. In our registry, these differences were not significant. This may indicate that the sex ratios in randomized clinical trials may be biased, as women might be more often excluded from reperfusion treatment of AMI [10].Baseline characteristics: Patients with ACS in our registry showed differences in baseline clinical characteristics between women and men. We confirm findings of multiple studies [1,2,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] which have shown that women with acute ischemic syndromes are older than men and are more likely to have a history of hypertension, diabetes, and congestive heart failure. Women are less likelyto be smokers and less likely to have had a prior MI, CABG or PCI. Pharmacotherapy: Several centers have reported gender differences in the medical treatment of cardiovascular disease, to the detriment of women [17]. Fewer women were prescribed beta-blockers for ACS in some studies [13,14]. We found the medical management of men and women with ACS similar, but fewer women were prescribed statins at the time of discharge despite of their higher levels of cholesterol compared to men. Lower use of clopidogrel in women corresponds with lower use of PCI but these findings may indicate lower adherence to guidelines when treating women with ACS. More women were taking digoxin and diuretics at the time of admission.
This fact is probably due to the greater proportion of women with hypertension and heart failure.
Angiographic characteristics: Similarly as in many studies [14,25,27] but in contrast to some other reports [18] we observed less severe angiographic extent of CAD and higher rates of clinically insignificant CAD among women with confirmed ACS [10]. The reason for the later finding could be more frequent coronary spasms or thrombosis on insignificant coronary plaque but also more frequent false diagnosis of ACS in women. Among those with significant coronary lesions, we found a lower rate of twoor three-vessel disease in women compared with men, which is also a common phenomenon in groups of patients with coronary heart disease [27]. These findings favoring women may be counterbalanced with smaller vessels and with other risk factors.
Invasive procedures: Frequently reported less aggressive therapy of ACS in women as compared to men can be a result of the general perception that women are at lower risk for heart disease and of uncertainty whether women with ACS benefit from the invasive treatment strategy as it is among men. This may negatively impact the management of high-risk women. As in other studies [14,19,[27][28][29][30][31][32] we found lower probability for women to be referred to CAG and subsequently to revascularization procedures.
Conservative therapy was more frequent in women.
The gender difference found in our study was mainly due to the lower rate of CAG among women with unstable angina and among women with any NSTE-ACS enrolled into regional registry. In PCI centers registry there was no gender difference in the use of invasive approach observed. Lower representation of women (35.6%) in PCI centers registry compared to peripheral registry (43.7%) also indicates that women are less likely than men to be referred to invasive investigation. The possible explanation for this gender difference include women's older age at presentation, greater risk profile, increased risk for an adverse procedural outcome, differences in symptoms and pain perception, lower predictive accuracy of noninvasive testing in women, patient preferences to undergo invasive procedures [5,20], physicians biases when dealing with women and physicians gender specific practices in the referral of women for cardiac catheterization [20]. Significantly fewer women underwent PTCA or CABG surgery. However once women were referred for cardiac catheterization, revascularization rates were similar to those in men, which is finding consistent with other studies. Among patients who were identified as having significant CAD on angiography, the proportion of patients who underwent PCTA or CABG was equal in both genders, which was also found in previous studies [14,19]. Among patients with STEMI the use of coronary angiography was high and in contrast to some studies [21] we have found no gender specific difference in the use of invasive procedures.

Outcomes
Evidence about the outcome of ACS in women is conflicting.
Some reports have concluded that women have a worse prognosis in comparison to men [1,17]. It is not clear whether this observation reflected differences in baseline characteristics [2,10], gender related pathophysiology [22] or differences in the diagnosis and treatment of ACS in men and women [21]. Reduced collateral blood flow in women might account for the higher rate of complications when coronary occlusion occurs. Some studies have attributed the worse prognosis of women to the older age, to the higher prevalence of arterial hypertension and diabetes. Other studies have found that the difference in mortality rate was independent of these factors. Furthermore more recent studies have found similar outcome in both genders [11] or even better prognosis for women with ACS [27].In our study the overall mortality of patients with any ACS was equal in men and women. Among STEMI patients the most of studies observed a higher early mortality in women compared to men [2,12,[23][24][25]29]. Some studies report, that primary PCI may eliminate these gender-specific differences in survival [31]. In our study 87% of patients with STEMI underwent primary PCI. There was only insignificant gender difference in hospital mortality in favor of men observed in this subgroup, 11.3% vs. 7.1%, (p=0,13).
With regard to NSTE-ACS, the existing evidence is contradictory.
Some studies have demonstrated similar outcomes of women and men [10,26] with no difference in the incidence of cardiovascular death, recurrent MI, or stroke [14]. In FRISC II study there was a trend toward a more severe outcome in the female group with NSTE-ACS, but in the multivariate analysis gender was not found to be an independent risk factor when adjusting for the baseline variables [13]. However, if the presence or absence of significant stenosis after angiography was also included in the statistical model, female gender was found to be an independent risk factor for death or MI [13]. In contrast Mueller found that women treated with very early aggressive revascularization with coronary stenting of the culprit lesion have a better long-term outcome as compared with men. In multivariate analysis he has found, that female gender reduced the risk of death or MI by 49% [27]. Among patients with unstable angina, female sex may even be associated with an independent protective effect [2]. We observed a trend to lower mortality of women with NSTEMI, (1.0% vs. 5.0%; p=0.15). Women in our study were more likely than men to have congestive heart failure during hospitalization, as was also found in several previous studies [12,28]. This finding may be related to the fact that higher percentage of women have a history of heart failure at presentation, and it may also reflect diastolic dysfunction being more pronounced in women [10].
Invasive versus conservative treatment: Important discussion continues about whether different outcomes exist for women with use of a routine invasive or selective invasive management strategy.
Some doubts have been raised whether the management of women and men with ACS should be similar. Female gender was reported to be risk factor for mortality and morbidity for Percutaneous Coronary Intervention (PCI) [29] and CABG [30]. Although in some studies the worse prognosis of women after cardiac interventions disappeared after adjustment to risk factors [31]. Analyses of The FRISC II [13], RITA-3 [15] randomized clinical trials found that women had less profit from an early invasive strategy in comparison to men. In RITA-3 study it appeared that women with ACS at lower risk and those with negative troponin levels tend to have excess of adverse events with invasive strategy. In FRISC II the prognosis of women was better than men in the conservative treatment group, while in the invasive treatment group in the presence of significant coronary stenosis the female gender was found to be independent risk factor for death and MI. The results from the mentioned trials conflict with the results of TACTICS-TIMI 18 trial in which women appeared to benefit as much as men from an early invasive strategy [16]. This is supported by the results of CRUSADE prospective registry in which women who were 14% less likely to receive early invasive management after ACS had a significantly higher in-hospital mortality with early conservative treatment (no early invasive vs. early invasive: 8.9% vs. 4.7%) [32].
Another study reports that aggressive revascularization offers a comparable survival benefit for both genders [11]. Mueller in his study even found that invasive treatment with PCI was associated with a significantly better outcome in women as compared with men with ACS [27].
The worse outcome of invasively treated women in FRISC seemed to be solely due to an excess hazard ratio in women undergoing CABG, as PCI to CABG ratio was 1:1 [13]. Therefore, the PCI: CABG ratio of the revascularization strategy might be an important contributor to gender differences in the outcome of patients with NSTE-ACS. Low rate of CABG in our group (PCI: CABG ratio was 8:1) may play role in favorable outcomes of invasively treated women. The seven days interval for invasive treatment in FRISC may be too long. Mueller found that women treated with very early aggressive revascularization with coronary stenting of the culprit lesion as the primary revascularization strategy have a better long-term outcome in comparison to men [27].
In our group the coronary angiography and subsequent coronary stenting of the culprit lesion as the primary revascularization method were performed within 3 days of admission in most patients. This treatment was associated with comparable outcome in women as compared to men.We observed a trend to higher inhospital mortality of women compared to men with early invasive treatment. Among patients with conservative treatment women's mortality was significantly lower then mortality of men. While the prognosis of women treated with invasive or conservative strategy did not differ, men treated conservatively had much worse prognosis compared to men treated invasively. Our results support the idea that early invasive strategy in women may be less advantageous then in men.

Study Limitations
Our analysis is derived from a prospective study of consecutive unselected patients rather than a randomized trial, but this may be particular valuable for the investigation of gender-based differences. Non-randomized study eliminates selection bias and eases the extrapolation of findings into clinical practice. Women are notoriously underrepresented in randomized controlled trials [27] of ACS. The numbers of patients are small to draw final conclusions.

Conclusion
Women are less often than men hospitalized for suspected ACS. Among those hospitalized and screened, the female gender predicts lower probability of ACS confirmation. Women with ACS have less advanced atherosclerosis, but often have important comorbidities associated with an increased invasive procedurerelated risk. Compared to men, women with ACS undergo less coronary angiography, angioplasty, and CABG surgery. Women suffer an increased rate of heart failure during hospitalization.
Although in many studies women with ACS consistently tend to have worse clinical outcomes, we observed indeed comparable outcomes in both genders in spite of higher risk profile of women.
Our results may reflect recent advances in angioplasty equipment which improved options for patients with smaller coronary and peripheral (access) arteries. In addition, the increased use of stents and adjunctive pharmacotherapy has improved outcomes in both women and men. Our study confirms that aggressive revascularization offers a comparable survival in the two sexes with satisfactory in-hospital outcomes. Treatment with the early angioplasty and coronary stenting of the culprit lesion gives satisfactory in-hospital results. While the prognosis of women treated with invasive and conservative strategy was equal, the prognosis of conservatively treated men was much worse. The men with NSTE-ACS seem to benefit more then women from the early invasive treatment.