Cardiovascular diseases are the leading cause of death in industrialised countries; among these, coronary artery disease (CAD) is the most prevalent and is associated not only with high mortality but also with substantial morbidity. Acute manifestations of CAD are ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), unstable angina pectoris (UAP) and sudden ischaemic death.1 Due to the similarity in pathophysiology and management, NSTEMI and UAP are usually referred to as non-ST-elevation acute coronary syndrome (NSTE-ACS). NSTE-ACS is the most frequent manifestation of ACS, more frequent than STEMI, and in relation to STEMI the rate has increased. Women with ACS more frequently present with NSTE-ACS compared with men.2 There are no definite figures for the incidence in Europe as a whole because of the absence of centralised health statistics; however, from surveys it has been estimated that the annual incidence of hospital admissions for NSTE-ACS is about three per 1,000 inhabitants.3,4 Although in-hospital mortality is higher in STEMI than NSTE-ACS, long-term mortality is similar.5 The NSTE-ACS population is heterogeneous with a wide variation in risk of death and new ischaemic events; therefore, risk stratification is a major part of the management of NSTE-ACS patients.
Revascularisation
Revascularisation is performed in the setting of NSTE-ACS to relieve symptoms and to prevent progression of myocardial damage and death. During the 1990s, there was intense debate as to whether an invasive approach with routine coronary angiography followed by revascularisation if feasible was superior to a more conservative approach with pharmacological stabilisation and coronary angiography if the patient experienced symptoms or signs of ischaemia (spontaneous or during a stress test).
These two treatment strategies have been compared in a number of randomised trials. Most6–10 but not all11–13 of the studies have been in favour of a routine invasive strategy. Today, early invasive treatment has become the strategy of choice in patients with NSTE-ACS, and is a class 1 recommendation in both American College of Cardiology/American Heart Association (ACC/AHA)14 and European Society of Cardiology (ESC)15 guidelines on NSTE-ACS, at least for patients with medium- or high-risk features.
However, gender differences in terms of benefit of an early invasive strategy have been intensively debated and the data are conflicting. Only three randomised trials comparing an early routine invasive strategy with a selective invasive strategy have pre-specified analyses according to gender: the Fragmin and fast Revascularization during InStability in Coronary artery disease (FRISC) II trial,16 the third Randomised Intervention Trial of Unstable Angina (RITA) 3 trial17 and the Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy – Thrombolysis In Myocardial Infarction (TACTICS-TIMI) 18 trial.18
In a fourth study, the Organisation to Assess Strategies in Acute Ischaemic Syndromes Investigators (OASIS) 5 Women Catheterisation Substudy (WCS),19 women were randomised to a routine invasive strategy or to a selective invasive strategy. The published paper also included a meta-analysis of earlier randomised trials. Moreover, a recent meta-analysis including eight randomised trials has addressed the question of whether there are differences between the genders in terms of the effect of a routine invasive strategy.20
Randomised Trials
In general, women in all of these trials were older than their male counterparts and had a higher rate of hypertension. On the other hand, the men were more often smokers and had a history of myocardial infarction.
The FRISC II16 trial randomly assigned 1,704 men and 749 women to an early invasive strategy with coronary angiography within seven days followed by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) if suitable. In contrast to a clear favourable outcome for men with a routine invasive strategy for the primary combined end-point of death/MI (9.6 versus 15.8%; p<0.001), there was no benefit in women (12.4 versus 10.5%; p = not significant [NS]). In a multivariate regression analysis adjusting for baseline differences between the genders, male sex was an independent risk factor for death/MI in the non-invasive strategy arm (odds ratio [OR] for death/MI women versus men 0.64, 95% confidence interval [CI] 0.43–0.97). On the other hand, in the routine invasive strategy arm female gender was associated with a worse outcome (OR for death/MI women versus men 1.46, 95% CI 0.96–2.23), although it did not reach statistical significance until further adjustment for presence of coronary stenosis (OR 1.72, 95% CI 1.11–2.65).
The RITA 317 trial included 682 women and 1,128 men. The results were similar to those of the FRISC II trial. While men had a lower incidence of the primary end-point of death/MI with a routine invasive strategy (7 versus 10.1%), there was a trend towards the opposite for women (8.6 versus 5.1%). An interaction test was significant (p=0.007). The numbers were similar for the secondary end-point, which was death. After adjustment for baseline variables in a multivariate analysis, the OR for death with an invasive strategy compared with a conservative strategy was 0.78 (0.44–1.41) for men and 2.43 (1.01–5.84) for women (interaction p=0.031).
In the TACTICS-TIMI 1818 trial, 2,220 patients (757 women and 1,463 men) were randomised to a routine invasive strategy or a selective invasive strategy. The primary outcome, a composite of death/MI/ re-hospitalisation for ACS, was significantly lower with an invasive strategy in men (15.3 versus 19.4%, OR 0.75, 95% CI 0.57–0.99), but did not reach statistical significance in women (17 versus 19.6%, OR 0.84, 95% CI 0.58–1.21). In a subgroup analysis in high-risk patients there was a similar benefit on the primary end-point of death/MI/ re-vascularisation in troponin-positive female patients (OR 0.56, 95% CI 0.32–0.97) and troponin-positive male patients (OR 0.53, 95% CI 0.35–0.79). However, in troponin-negative women there was a possible indication of harm (OR 1.46, 95% CI 0.78–2.72) that was not seen in men (OR 1.02, 95% CI 0.64–1.62).
Finally, in the OASIS 5 WCS,19 women were randomised in a 2x2 factorial design to treatment with fondaparinux versus enoxaparin and also to a routine invasive strategy versus a selective invasive strategy. Unfortunately, only a limited number of participating centres contributed to the substudy; therefore, only 184 patients were included. There was no statistical difference between the routine invasive and the selective invasive strategies in the primary outcome measure of death/MI/stroke (16 versus 12%, hazard ratio [HR] 1.36, 95% CI 0.66–3.20) or the secondary end-point of death/MI during one year (14.1 versus 10.9%, HR 1.45, 95% CI 0.59–3.13). However, there was a significantly higher rate of death with an invasive strategy at one year (8.8 versus 1.1%, HR 9.01, 95% CI 1.11–72.90).
Meta-analyses
The OASIS 5 WCS paper,19 published in the European Heart Journal 2009, included a meta-analysis. Earlier randomised trials with separately published data for women and men, data from the most recent study, Invasive versus Conservative Treatments in Unstable Coronary Syndromes (ICTUS), and data from OASIS 5 WCS were included in the meta-analysis (2,692 women and 5,179 men). There was a clear benefit with a routine invasive strategy compared with a selective invasive strategy in men for death/MI (OR 0.78, 95% CI 0.66–0.93) that could not be seen in women (OR 1.18, 95% CI 0.92–1.53), with a significant p-value for interaction (p=0.001). Also, in terms of death men had a significantly better outcome with a routine invasive strategy (OR 0.70, 95% CI 0.51–0.96), while the opposite was indicated in women (OR 1.51, 95% CI 0.73–1.18). The p-value for interaction was 0.012. Another meta-analysis by O’Donoghue et al. included eight trials (3,075 women and 7,075 men).20 The OR for the composite of death, MI or re-hospitalisation with ACS (routine invasive versus selective invasive) was 0.81 (95% CI 0.65–1.01) for women and 0.73 (95% CI 0.55–0.98) in men, without significant heterogeneity between the genders (interaction p=0.26). There was no statistically significant difference in outcome with a routine invasive strategy versus a more selective invasive strategy in the end-point of death/MI either for men (OR 0.87, 95% CI 0.61–1.23) or for women (OR 1.02, 95% CI 0.67–1.55).
A separate analysis was performed to assess the benefit to patients with or without elevated biomarkers in terms of the primary outcome measure: death/MI/re-hospitalisation for ACS. Among biomarker-positive patients, both women (OR 0.67, 95% CI 0.50–0.88) and men (OR 0.56, 95% CI 0.46–0.67) had a favourable outcome with an invasive strategy. Biomarker-negative male patients had a directionally consistent but weaker benefit with a routine invasive strategy (OR 0.72, 95% CI 0.51–1.01), while there was no obvious benefit in women (OR 0.94, 95% CI 0.61–1.44).
Discussion
There are several possible reasons for the differences in benefit between men and women with NSTE-ACS from an invasive strategy. A common finding in the FRISC II, RITA 3 and TACTICS-TIMI 18 was that women have less obstructive CAD. In the routine invasive strategy arms, the rate of no significant stenosis was lower in men (9.5 versus 24.6%, 12 versus 37% and 10 versus 18%, respectively), while the proportion of three-vessel disease was higher in men (26.3 versus 20.9%, 26 versus 16% and 37 versus 26%, respectively) in FRISC II, RITA 3 and TACTICS-TIMI 18.
Patients without significant stenosis have been shown to have a better outcome, and in the FRISC II trial these patients had an excellent prognosis with no deaths during one-year follow-up. Obviously, the relative paucity of obstructive CAD may dilute the treatment benefit with an invasive strategy. The lower event rate in women managed in a selective invasive way in FRISC II and RITA 3 may be explained by the high proportion of women with a low degree of CAD. However, this is challenged by the findings in the TACTICS-TIMI 18 trial, in which there was no difference in outcomes between men and women in the selective invasive arm despite a similar difference in the rate of obstructive CAD.
There was a difference between the genders not only in the severity of CAD, but also in the proportion of patients with elevated markers. In both FRISC II and TACTICS-TIMI, 18 men were significantly more likely to have elevated troponin T compared with women: 62 versus 47% and 57 versus 47%, respectively. Troponin is a marker of myocardial necrosis and is predictive of the degree of CAD and even probability of visible thrombus on the angiogram, indicative of plaque rupture.21 In TACTICS-TIMI 18, the benefit from an invasive strategy was similar in men and women with elevated markers. However, among troponin-negative men the effect of a routine invasive strategy was weaker but directionally consistent with troponin-positive men, while potential harm was indicated in troponin-negative women. These data were further supported in the meta-analysis by O’Donoghue et al., where the benefit of an invasive strategy in women appeared to be restricted to patients with elevated markers. The difference between the genders in the numbers of troponin-negative patients as well as the difference in the magnitude of benefit from an invasive strategy in troponin-positive patients may well explain a substantial part of the overall difference between men and women in the effect of a routine invasive strategy.
Due to the study design, in the TACTICS-TIMI 18 a glycoprotein (GP) IIb/IIIa inhibitor was administered to all patients, and this has been suggested as a reason for improved outcome with an invasive strategy in women. However, the benefit with GPIIb/III inhibitor treatment in women with NSTE-ACS has been questioned, especially in troponin-negative women.22 There are alternative reasons for differences in effect derived from a routine invasive strategy between FRISC II, RITA 3 and TACTICS-TIMI 18, such as differences in risk factor profile and risk associated with invasive procedures.
In a large number of trials, both randomised and registry, conservatively treated women had better outcomes than their male counterparts. Although admittedly speculative, could it be that men with a higher proportion of elevated troponin actually benefited more than women from routine GPIIb/IIIa treatment in TACTICS-TIMI 18? This would explain the observed lack of difference between women and men in the selective invasive arm.
Risk associated with invasive procedures may differ between the genders. Several earlier trials have indicated higher risk associated with an invasive strategy for women. Whether the observed differences in these studies were explained by differences in coronary artery size, body size or co-morbidity is still debated.23 The higher event rate in women compared with men treated with a routine invasive strategy in the FRISC II trial seemed largely due to an increased rate of death (9.9 versus 1.2%) and recurrent MI (12 versus 5%) in women who had CABG surgery performed.
The ratio of PCI to CABG was approximately one in the invasive arm in the FRISC II trial, while in the invasive arm in TACTICS-TIMI 18 trial there was no significant difference between men and women with an invasive strategy and the PCI/CABG ratio was about two, which lends support to the notion that PCI/CABG ratio in revascularised patients may be an important contributor to gender differences in invasively treated patients with NSTE-ACS. Not only was there an increased mortality rate in women who had a CABG performed in FRISC II compared with TACTICS-TIMI 18 (9.9% [one year] versus 5.3% [six months]), but also in men the mortality was substantially lower (1.2% [one year] versus 4.5% [six months]), which contributes to understanding the differences between the two trials in the outcome.
In terms of PCI-treated patients, there was no difference in the death rate between men and women in FRISC II (1.5 versus 1.2%; p=NS) or death/MI (15 versus 14.6%; p=NS). Similar results were obtained in TACTICS-TIMI 18, where there was no difference in death/MI at six months (10.7% in women versus 10.9% in men; p>0.99). An observed lack of difference between men and women undergoing PCI is supported by some more recent observational studies.24 However, a higher bleeding complication rate associated with PCI has repeatedly been observed in women. For example, in the TACTICS-TIMI 18 the rate of major bleeding was substantially higher in women, even after adjustment for differences in baseline variables (8.3 versus 2.9%, adjusted OR 3.6, 95% CI 1.6–8.3; p=0.001).
Data from OASIS 5 WCS, in which eight of 11 major bleedings during follow-up occurred in the 80 patients treated with PCI compared with one major bleed among 78 patients treated conservatively, also indicate a high risk of bleeding associated with PCI. Increased bleeding rates have been reported in ACS patients treated with GPIIb/IIIa inhibitors, especially in combination with thienopyridines25 and among women.26 Several recent trials have highlighted bleeding as an important predictor of both short- and long-term outcome in patients with ACS.27–29
Conclusion and Clinical Implications
A female population compared with a male population with NSTE-ACS appears to receive less benefit from a routine invasive strategy. The reason is most likely a combination of several factors, among them the difference between the genders in risk profile and differences in risk associated with invasive procedures. Both men and women at high risk, defined as elevated markers of myocardial necrosis, seem to benefit from an invasive strategy. In low-risk patients with ACS there has been an indication of harm with a routine invasive strategy in women that could not be seen in men. Prospective studies to elucidate whether there are true differences in the effects of different strategies according to gender and the importance of differences in underlying pathophysiology and co-morbidity and effect with a certain treatment strategy are strongly needed to identify the most appropriate treatment for men and women, respectively.
A challenge for future research will be to find ways to identify patients with the highest net clinical benefit from an early invasive strategy, maybe by a multimarker approach as suggested in a sub-study of the TACTICS-TIMI 1830 or, preferably, by novel markers that are more specific in identifying plaque rupture. Research efforts should also be directed at identifying predictors of complications and development of invasive techniques to minimise complications. The clinical challenge is to identify individual patients with the highest risk of ischaemic events without unreasonably elevated early risk of complications with an invasive strategy. For example, actions to minimise bleeding complications, including dose adjustments according to renal function, weight and age, are of utmost importance for both genders but particularly for women. However, an individually tailored treatment strategy to balance early procedural risk with long-term reduction of cardiac events will benefit both men and women with NSTE-ACS.