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Abstract
Background: Data comparing survival outcomes for women versus men transported for pPCI were absent.
Objectives: To assess the impact of gender on 30-day mortality of patients with STEMI transported for pPCI.
Methods: The data from the PRAGUE-1 and PRAGUE-2 trials were analysed. Studies compared thrombolysis in the community hospital and pPCI after transportation to cardiocentre. A group of 520 patients treated with thrombolysis, and 530 transported for pPCI, were analysed.
Results: Women were older, with a higher risk profile. They had longer ischaemia time. Mortality of patients treated with TL was significantly higher in women than in men (15% vs 9%, p = 0.043). There was no significant gender difference in mortality in the PCI group (8.2% of women vs 6.2% of men, p = 0.409). Mortality of women treated with on-site TL was nearly twice as high as mortality of women transported for pPCI (p = 0.043). After adjustment in a multivariate model the odds ratio for mortality in women was 0.74 (95% CI 0.26 to 2.05; p = 0.556).
Conclusion: Long-distance transportation of women with STEMI from a community hospital to a tertiary PCI centre is a significantly more effective treatment strategy than on-site TL. Gender did not determine survival in patients transported for pPCI.
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Primary percutaneous coronary intervention (pPCI) has been shown to significantly improve the survival of patients with an ST elevation acute myocardial infarction (STEMI), and to be superior to thrombolytic therapy in terms of the immediate restoration of normal coronary flow in the infarct-related artery as well as a reduction in recurrent ischaemia or reinfarction.1 2 There are a few reports with conflicting data regarding the impact of pPCI on early outcomes in women versus men with acute STEMI.3–6
In the usual clinical situation, most patients experiencing an AMI initially present to community hospitals. Transfer to a PCI centre for catheter-based reperfusion has been shown to be superior to on-site thrombolysis (TL).7–9 However, data comparing survival outcomes for women versus men with STEMI transported for pPCI are lacking. The objective of the present study was to assess the impact of gender on the survival of patients with STEMI transported (long-distance) for pPCI.
METHODS
The data from the PRAGUE-17 and PRAGUE-28 trials were analysed with a focus on gender differences and final clinical outcome. Studies compared on-site TL in community hospitals without a catheter laboratory and immediate PCI after (long-distance) transportation to a cardiocentre. We analysed a group of 520 patients treated with TL and 530 transported for PCI.
PRAGUE trials data
The PRAGUE-1 trial7 enrolled 300 patients with STEMI who presented within 6 hours of symptom onset to a community hospital without a catheter laboratory. They were randomised into three groups: TL given in the community hospital (n = 99), TL during transportation to a PCI center (facilitated angioplasty, n = 100) and transport for pPCI without lytics (n = 101). The facilitated-PCI group was excluded from this analysis, because it was not a part of the PRAGUE-2 trial. The PRAGUE-2 trial8 enrolled 850 patients who presented within 12 hours of symptom onset to a community hospital without a catheter laboratory. They were randomised into two groups: TL in the community hospital (n = 421) or transportation for pPCI without lytics (n = 429). More detailed baseline characteristics and study protocol characteristics are in the original papers describing the study results.7 8
Studies’ end points
The primary end point of the PRAGUE-1 trial was a combined clinical end point of death/reinfarction/rehospitalisation/heart failure at day 30 and year 1. In the PRAGUE-2 trial, the primary end point was 30-day mortality. Secondary end points in PRAGUE 2 were death/reinfarction/stroke at 30 days (combined end point) and 30-day mortality among patients treated within 0–3 h and 3–12 h after symptom onset.
Statistical analysis
Differences between men and women were assessed using the χ2 test in contingency tables or the Fisher exact test (for too few numbers) for categorical data as appropriate, and the Wilcoxon rank sum test for continuous data. Multivariable analyses were performed by using a logistic regression model with adjusting odds ratio. All statistical analyses were performed using SPSS, Version 12.0 software (SPSS Inc.). All p values are two-tailed. A p value of less than 0.05 was considered significant.
RESULTS
Baseline characteristics of patients according to sex are presented in table 1. The proportion of women in both groups was less than one-third; 29.4% in the TL group, 30% in the pPCI group. The largest proportion of women was in the age group from 65 to 74. The largest proportion of men was in the age group younger than 65 (fig 1). Women were older than men (p<0.001), with a higher prevalence of hypertension (TL group p = 0.55; PCI group p<0.001) and diabetes (TL group p<0.001; PCI group p<0.007). There were no differences in the history of previous myocardial infarction. Significantly fewer women were cigarette smokers (TL group p<0.001; PCI group p<0.001). They also had acute heart failure (Killip>1) more often at admission (p = 0.3, OR 1.3, 95% CI 0.8 to 2.1).
Time delay
The treatment delays are shown in table 2 and in fig 2. Women had significantly longer delays from the onset of symptoms to randomisation: a median 27 min longer than men in the TL group (p = 0.012) and 43 min longer than men in the PCI group (p = 0.004). We did not find any correlations between prehospital delay and Killip classification (p = 0.994 in the PCI group, p = 0.54 in the TL group) or between prehospital delay and age (Spearman correlation coefficient 0.133 in the PCI group and 0.101 in the TL group).
Infarct characteristics, angiographic results and procedural success
An anterior wall infarction was suffered by the same proportion of women and men in the TL group (39%), but by more women in the PCI group, though not significantly (45.3% versus 40.2%) (table 1). The mean echocardiographic left ventricular ejection fraction at admission was not significantly different between women and men treated by either TL or pPCI (table 1). Angiographic results and procedural success are detailed in table 3. There were no significant gender differences in angiographic characteristics. Women were more likely than men to have no severe coronary artery stenosis (1.9% vs 4.4%, p = 0.09, OR 2.4, 95% CI 0.83 to 6.94). In the PCI group, a stent was implanted whenever anatomically suitable (vessel ⩾3.0 mm in diameter, no extreme tortuosity), or when there was a suboptimal result (as assessed by the surgeon) after balloon angioplasty. Usage of intracoronary stents differed significantly between women and men (49% in women vs 59.8% in men, p = 0.022, OR 0.65, 95% CI 0.45 to 0.94).
Clinical outcomes
Clinical end points at day 30 are presented in table 4 and fig 3. Mortality of patients treated with TL was significantly higher in women than in men (15% vs 9%, p = 0.043). There was no significant gender difference in mortality in the PCI group (8.2% of women vs 6.2% of men, p = 0.409). Mortality of women treated with on-site TL was nearly twice as high as mortality of women transported for pPCI (p = 0.043).
The unadjusted odds ratio for 30-day mortality was higher for women in both treatment groups. Women with STEMI treated with TL were 79% more likely to experience a fatal outcome than men (OR 1.79, 95% CI 1.01 to 3.17, p = 0.043). For catheter-based reperfusion therapy, the unadjusted risk of death was non-significantly higher (by 35%) for women than for men (OR 1.35, 95% CI 0.66 to 2.73, p = 0.409). We compared 30-day mortality between women and men with adjustment for baseline, clinical, and angiographic characteristics by means of multiple logistic regression analysis. We implemented all covariates which could influence the outcome (gender, age, time delay, smoking status, history of previous AMI, comorbidity, localisation of infarction, Killip classification, angiographic characteristics, PCI procedural technical success).
In the TL group (fig 4), correction for time delay caused a small reduction in the excess risk for women (OR 1.75, 95% CI 0.98 to 3.1, p = 0.057). With adjustment for age, however, the risk attributable to being female diminished as the hazard ratio fell to 1.27 (95% CI 0.69 to 2.33, p = 0.446). Further corrections for all prognostically important covariates modified the adjusted hazard ratio for women only minimally (1.19, 95% CI 0.54 to 2.63, p = 0.67).
In the case of transportation for pPCI, adjustment for time delay had no influence on the odds ratio for 30-day mortality (OR 1.35, 95% CI 0.67 to 2.75, p = 0.404) (fig 5). After adjustment in a multivariate model for variables influencing prognosis, the odds ratio for mortality in females was 0.74 (95% CI 0.26 to 2.05, p = 0.56). Therefore, gender did not influence survival in patients transported for pPCI.
Compared with men, women treated with TL had a higher risk of stroke (OR 4.57, 95% CI 1.32 to 15.8, p = 0.015). With PCI this gender-related risk almost disappeared (to only 0.6%). In both sexes, pPCI reduced the risk of reinfarction, in women by 75% and in men by 70%.
DISCUSSION
In accordance with other clinical trials3 4 5 10 and a European survey,11 the percentage of women with STEMI was smaller compared with men in the PRAGUE-1 and PRAGUE-2 trials. Multiple studies3–5 10 11have shown that women with acute myocardial infarction have a higher risk profile than men. Women tend to be older than men and are more likely to have a history of hypertension, diabetes, angina, and acute heart failure. They are less likely to be smokers and less likely to have had a prior infarction. Except for the incidence of previous myocardial infarction, our study confirms these findings. Women with STEMI presented at the hospital after a significantly longer delay since symptom onset. There were no significant differences in the numbers or distribution of diseased coronary vessels. Interestingly, women were more likely to have an angiogram showing no significant coronary stenosis. The initial and final TIMI flow grades also did not differ significantly between the sexes.
In line with previous reports, women with STEMI had a higher risk for 30-day mortality, with the gender-related difference depending on the mode of reperfusion strategy. The PRAGUE-1 and PRAGUE-2 studies reflected standard clinical practice. They compared patients presenting to a community hospital without a catheterisation facility and receiving on-site TL with transportation to a hospital where they received pPCI.
Women treated with on-site TL had significantly higher short-term mortality than men (p = 0.043, unadjusted OR 1.79). One possible association was that TL is a more time-dependent reperfusion strategy, and women had a significantly longer period of ischaemia. Surprisingly, the correction for time delay in patients treated with TL resulted in only a small reduction in the excess risk for women (OR 1.75, p = 0.057) (fig 4). However, adjustment for age eliminated two-thirds of the female-gender-associated excess mortality (OR 1.27, p = 0.446). Further correction for all prognostically important covariates modified the adjusted odds ratio for women minimally (1.19, p = 0.67). By our analysis, there was at most only a small independent effect of sex on early mortality in patients treated with TL. As is consistent with the published analysis of the GUSTO-1 trial,12 older age was the most powerful determinant of 30-day mortality in women treated with TL. The data from the PRAGUE-1 and PRAGUE-2 studies did not allow an adjustment for body mass index to be made. We hypothesise that correction for this variable can be important in the case of non-weight-adjusted doses of streptokinase.
In the group of patients with STEMI transported (long-distance) for pPCI, there was no significant gender difference in mortality (p = 0.409, unadjusted OR 1.35). Also, in this treatment group, women took longer than men to arrive at the community hospital. As the regression analysis showed, correction for time delay did not have any influence on the odds ratio for 30-day mortality of women transported for pPCI (OR 1.35). After adjustment for all prognostically important covariates, female gender per se was not an independent risk factor for death.
Primary PCI is more effective than thrombolytic therapy for the treatment of STEMI.1 2 Published data about the gender-related differences in the effectiveness of reperfusion therapy for STEMI are controversial.3 4 6 12 13 There is conflicting evidence as to whether gender is an independent predictor for mortality of patients with STEMI treated with catheter-based reperfusion.3 5 6 14 Data comparing survival outcomes for women versus men with STEMI transported for pPCI are lacking. Our analysis has confirmed that there are no significant gender-related differences in the effectiveness of pPCI after (long-distance) transportation to a PCI centre. Compared with on-site TL, the benefit from this strategy was higher in women with STEMI than in men (relative risk reduction for women 45%, relative risk reduction for men 31%). Mortality of women treated with on-site TL was nearly twice as high as mortality of women transported for pPCI (p = 0.043). Neither longer pre-hospital delay, advanced age, nor the higher risk profile of women significantly diminished the benefit from transportation for PCI.
The usage of intracoronary stents was significantly lower in women (p = 0.022) in the PRAGUE-1 and PRAGUE-2 trials. Also, the optimal procedural success rate was higher in men (p = 0.069). As a recently published study has shown, primary stenting significantly reduced major adverse cardiac events (MACE) in women.14 Routine use of contemporary interventional treatment techniques will enhance the survival benefit associated with the transportation of women with STEMI to PCI centres.
The longer time delays from symptom onset to the seeking of medical attention are well documented for women and are the focus of current public education programmes. Nevertheless, the time from symptom onset to the initiation of reperfusion therapy in large-scale clinical trials has remained unchanged over the past decade.15 Therefore, the observation that longer pre-hospital delay in women did not markedly affect the benefit from pPCI as compared with men, even with the inherent time delay associated with transporting patients (long-distance) to PCI centres, could be worthy of note.
CONCLUSION
Long-distance transportation of women with STEMI from a community hospital to a tertiary PCI centre is a significantly more effective treatment strategy than on-site TL. Gender did not determine survival in patients transported for pPCI. Neither longer pre-hospital delay, advanced age, nor the higher risk profile of women significantly diminished this benefit from transportation to PCI.
LIMITATION
It was not possible to perform Cox regression analysis because exact timing of events was not available.
Acknowledgments
This paper was supported by the Charles University Prague Research Project nr. MSM 0021620817 awarded by the Ministry of Education, Youth and Physical Education of the Czech Republic. The authors acknowledge the contribution of numerous Czech physicians and nurses from the centres participating in the PRAGUE trials. Their complete list is in the two original papers.7,8 The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors wish to express sincere gratitude to Dr S Wimmerova (Institute for Preventive and Clinical Medicine, SHU Bratislava) for help with statistical analysis.
REFERENCES
Footnotes
Competing interests: None.