Author + information
- Received August 18, 2014
- Revision received December 16, 2014
- Accepted December 18, 2014
- Published online May 1, 2015.
- Marco De Carlo, MD, PhD∗∗ (, )
- Nuccia Morici, MD†,
- Stefano Savonitto, MD‡,
- Vincenzo Grassia, MD§,
- Paolo Sbarzaglia, MD‖,
- Paola Tamburrini, MD¶,
- Claudio Cavallini, MD‖,
- Marcello Galvani, MD#,
- Paolo Ortolani, MD∗∗,
- Stefano De Servi, MD†† and
- A. Sonia Petronio, MD∗
- ∗Cardiac Catheterization Laboratory, Cardiothoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- †First Division of Cardiology, Ospedale Niguarda Ca’ Granda, Milan, Italy
- ‡Division of Cardiology, Ospedale Manzoni, Lecco, Italy
- §Division of Cardiology, Ospedale S. Maria delle Grazie, Pozzuoli, Italy
- ‖Department of Cardiology, Ospedale S Maria della Misericordia, Perugia, Italy
- ¶INRCA, Ancona, Italy
- #Division of Cardiology, Ospedale Morgagni–Pierantoni, Forlì, Italy
- ∗∗Division of Cardiology, Policlinico S. Orsola-Malpighi, Bologna, Italy
- ††Cure Intensive Coronariche, IRCCS Policlinico S. Matteo, Pavia, Italy
- ↵∗Reprint requests and correspondence:
Dr. Marco De Carlo, Emodinamica, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy.
Objectives This study sought to investigate sex-related differences in treatment and outcomes in elderly patients with non–ST-segment elevation acute coronary syndromes (NSTEACS).
Background Female sex and older age are usually associated with worse outcome in NSTEACS. The Italian Elderly ACS study enrolled NSTEACS patients aged 75 years of age and older in a randomized trial comparing an early aggressive with an initially conservative strategy and in a registry of patients with ≥1 exclusion criteria of the trial.
Methods We compared sexes in the pooled populations of the trial and registry.
Results A total of 645 patients (313 from the trial and 332 from the registry), including 301 women (47%), were enrolled. Women were slightly older than men (82.1 ± 5.0 years vs. 81.2 ± 4.5 years; p = 0.02), had lower hemoglobin levels (12.5 ± 1.6 g/dl vs. 13.3 ± 1.9 g/dl; p < 0.001), and underwent fewer coronary revascularizations during the index admission (37.2% vs. 45.0%; p = 0.04). In-hospital adverse event rates were similar in both sexes; severe bleeding was uncommon (0.3% vs. 0%). The 1-year primary endpoint (composite of death, nonfatal myocardial infarction, disabling stroke, cardiac rehospitalization, and severe bleeding) occurred less often in women (27.6% vs. 38.7%; p < 0.01). Women not undergoing revascularization showed a 3-fold higher mortality, both in-hospital (8.5% vs. 2.7%; p = 0.05) and at 1 year (21.6% vs. 8.1%; p = 0.002).
Conclusions Elderly women had a similar in-hospital outcome and better 1-year outcome compared with men. Coronary revascularization in women was associated with lower 1-year mortality, without an increase in severe bleeding. Elderly women with NSTEACS should always be considered for early revascularization.
Subgroup analyses of randomized, controlled trials (RCTs) and registries of acute coronary syndromes (ACS) show less benefit from an invasive approach in women than in men (1–3). However, women represent a minority of the study populations, are significantly older than men, and experience more comorbidities.
Moreover, little is known about sex-related differences in elderly patients because elderly patients are under-represented in RCTs. The Italian Elderly ACS study consisted of an RCT comparing an early aggressive with an initially conservative strategy in patients 75 years of age and older with non–ST-segment elevation ACS (NSTEACS) (4), and a parallel registry of patients who fulfilled the inclusion criteria of the trial but had at least 1 exclusion criterion. The aim of the present study was to investigate sex-related differences in the pooled populations of the study.
Study design and population
Details regarding study design and population of the Italian Elderly ACS were previously published (4,5). The primary endpoint was the composite of all-cause mortality, nonfatal myocardial infarction (MI), disabling stroke, and repeat hospitalization for cardiovascular causes or severe bleeding within 12 months.
Results are presented as number and percentage for categorical variables, and mean ± SD for continuous data. Comparison of categorical variables between groups was performed using the chi-square test or the Fisher exact test, whereas the Student t test was used for continuous variables. To investigate the sex effect on the primary endpoint in the trial and registry population, we pooled all data using a meta-analytical approach, assuming a series of different treatment effects because of different baseline characteristics. We applied the random-effects model to account for the variance within each population and between trial and registry. Survival plots and log rank tests were used to determine and compare the 1-year cumulative risk of events according to sex and age. The independent predictors of the 1-year primary composite endpoint were evaluated using the Cox proportional hazards model.
The study population consisted of 645 patients: 313 in the RCT and 332 in the registry. The overall heterogeneity of the populations of the trial and registry was very low (I2 = 0%). When comparing the 301 women with the 344 men enrolled in the pooled populations, the baseline clinical characteristics were remarkably similar, with only few statistically significant differences, including older age, lower hemoglobin levels, and higher left ventricular ejection fraction in women (Table 1). The key variables of ischemic electrocardiogram (ECG) changes and increased troponin levels were identical in men and women.
Women had nonsignificantly lower rates of coronary angiography, but significantly lower rates of coronary revascularization (37% vs. 45%; p = 0.04) (Table 1). Conversely, medical treatment did not differ between sexes. More than 70% of all interventions were performed via the radial artery.
No significant differences between sexes were observed regarding in-hospital adverse events, including death, MI, stroke, and severe bleeding (Table 1). Only 1 woman experienced a severe bleeding event during hospitalization (0.3%).
The rates of overall and cardiovascular death, MI, stroke, and severe bleeding were also similar between sexes at 1-year follow-up, but the rate of rehospitalization for cardiovascular causes was almost one-half for women (9.3% vs. 16.0%; p = 0.01), thus driving the primary endpoint toward a significantly lower rate (27.6% vs. 38.7%; p < 0.01) (Table 1, Figure 1). The Kaplan-Meier freedom from the primary endpoint at 1 year was 73 ± 2% for women versus 67 ± 2% for men (p < 0.01) (Figure 2).
Male sex was an independent predictor of the primary endpoint (hazard ratio [HR]: 1.59, 95% confidence interval [CI]: 1.18 to 2.15; p = 0.003), together with older age (HR: 1.04 per year, 95% CI: 1.01 to 1.07; p = 0.016), lower left ventricular ejection fraction (HR: 1.04 per percentage point, 95% CI: 1.02 to 1.05; p < 0.001), and lower hemoglobin levels (HR: 1.16 per g/dl, 95% CI: 1.07 to 1.25; p < 0.001).
Differences between trial and registry
Women enrolled in the registry had worse risk profiles compared with women enrolled in the trial, with significantly older age, lower estimated glomerular filtration rate, and higher rates of increased troponin levels and of ischemic ECG changes (Table 2). Coronary angiography was performed in 55% of women in both the trial and registry; however, the rate of revascularization was lower in the registry (33.3% vs. 41.4%; p = 0.15). Clinical outcomes were similar between trial and registry populations both in-hospital and at 1 year (Table 2).
When comparing the 226 women with non–ST-segment elevation myocardial infarction (NSTEMI) with the 75 women with unstable angina enrolled in the trial and registry, no significant differences were observed regarding baseline profile and treatment characteristics, except for worse renal function (estimated glomerular filtration rate, 44.1 ± 18.3 ml/min vs. 52.0 ± 20.4 ml/min; p < 0.01). Coronary angiography and revascularization rates were 56.6% and 38.9% for NSTEMI and 52.0% and 32.0% for unstable angina. In-hospital clinical outcomes were similar, but the 1-year primary endpoint occurred more frequently for NSTEMI (30.1% vs. 20.0%; p = 0.09), mainly driven by higher mortality (19.0% vs. 9.3%; p = 0.05).
Revascularization versus nonrevascularization
When comparing the 111 women who underwent any kind of coronary revascularization during the index admission with the 190 women who were not revascularized, the latter had a significantly worse risk profile, including older age and lower estimated glomerular filtration rate (Table 3). In-hospital mortality was significantly higher among nonrevascularized women (8.5% vs. 2.7%; p = 0.05), whereas the MI rate was higher in the revascularized group (2.7% vs. 1.6%; p = 0.51) (Table 3). There were only 1 severe bleeding event and 1 stroke, and both occurred in the nonrevascularized group. At 1-year follow-up, nonrevascularized women had a 3-fold higher mortality rate (21.6% vs. 8.1%; p = 0.002), mainly cardiovascular (17.3% vs. 6.3%; p = 0.002). No significant differences were observed concerning other adverse events.
The main findings of the present study are the following: 1) when sex-related difference in age is eliminated by inclusion criterion, the baseline clinical characteristics are remarkably similar between sexes, including renal function, diabetes, ischemic ECG changes, and troponin levels, whereas a significantly lower ejection fraction in men probably reflects a longer ischemic history, with previous revascularizations; 2) despite these similarities, coronary revascularization is still significantly performed less in women; 3) the rate of in-hospital adverse events is similar between sexes; 4) the 1-year outcome was significantly worse in men, driven by a higher rate of cardiac rehospitalizations (mainly congestive heart failure); and 5) women who are not revascularized have a 3-fold higher in-hospital and 1-year mortality rate compared with revascularized women.
The Italian Elderly ACS study included one of the largest prospectively enrolled populations of truly elderly ACS patients (6,7), with a very low heterogeneity between trial and registry.
In the pooled population, women underwent significantly fewer revascularizations compared with men; this difference derives from a slightly lower rate of coronary angiography, but also from a lower rate of revascularization after angiography. Notably, the rates of in-hospital adverse events were similar between sexes. This finding is in contrast with previous reports of higher in-hospital mortality and morbidity in women older than 75 years of age undergoing primary percutaneous coronary intervention (PCI) (8). In the broader setting of NSTEACS, our study shows a similar short-term outcome between sexes and an even better 1-year clinical outcome in women, questioning the idea that elderly women may be too fragile to tolerate an invasive therapeutic approach. In fact, in a recent report describing age-specific sex differences in in-hospital mortality after an ACS, mortality difference by sex decreased with age, with women having marginally better outcomes at 70 years of age and older in NSTEMI (9). Similarly, no sex difference in 1-year mortality was observed in the older age group of a large population of primary PCI patients (10). A possible explanation for these findings may be the longer history of coronary disease in elderly men compared with women, as also shown in our study.
A surprising finding in our study was the low rate of in-hospital severe bleeding in women. We believe that the use of the radial artery access in more than 70% of the patients may explain such a finding, at variance with former studies describing female sex as a risk factor for bleeding in ACS (11) and for PCI (12), although such a sex-related risk decreased over the past years. Our study is in agreement with the Acute Coronary Syndrome Prospective Audit (ACACIA) registry, in which age 75 years and older was not a risk factor for bleeding (13).
As expected, women enrolled in the registry showed a significantly worse profile compared with women enrolled in the trial. However, the rates of coronary angiography and revascularization did not differ significantly between trial and registry. Moreover, the prevalence of in-hospital and 1-year adverse events was comparable between groups, showing that the Italian ACS Elderly RCT did not enroll a low-risk population.
Revascularization versus no revascularization
Large NSTEACS registries showed that patients older than 75 years of age are less likely to receive an early invasive strategy and be revascularized, although their absolute accrued benefit appears to be the highest (6,13). In particular, in the ACACIA, only 30% of elderly patients underwent revascularization. In the present study, the rates of coronary angiography and revascularization are the highest reported in the literature for elderly patients, being 56% and 37% in women and 62% and 45% in men, respectively. This finding confirms the trend toward a more appropriate management of elderly patients with an NSTEACS, which should not differ from that of younger patients and should include coronary angiography and revascularization, whenever appropriate. In fact, myocardial revascularization during the index admission was strongly associated with a better 1-year clinical outcome in elderly women. In the Italian Elderly ACS trial, an early aggressive approach was associated with a clinical benefit only in patients with increased troponin at baseline. In the present analysis, the addition of the registry data, with an 89% rate of increased troponin on admission, enhanced the correlation between early revascularization and better 1-year prognosis; in particular, women undergoing revascularization showed a 3-fold lower cardiac mortality at 1-year compared with those not revascularized.
The present analysis has the obvious limitation of pooling together patients enrolled in the RCT and in the parallel registry, although the 2 populations were quite homogeneous. Therefore, despite the fact that coronary revascularization was associated with better survival at multivariable analysis, a number of clinical and angiographic characteristics of the patients may have impacted clinical decision-making. In addition, as all patients enrolled in the trial and registry had to be able to sign an informed consent, our data may not apply to the frailest of elderly patients.
Our study shows that elderly women presenting with an NSTEACS have a short-term outcome similar to that in men and a better 1-year clinical outcome. Moreover, women undergoing coronary revascularization had only one-third of the mortality rate observed in women not undergoing revascularization, without the higher rates of severe bleeding. Therefore, elderly women with an NSTEACS should not be denied an evidence-based diagnostic and therapeutic approach because of an alleged excess in in-hospital mortality and severe bleeding.
WHAT IS KNOWN? Female sex and older age are usually associated with worse outcome in NSTEACS.
WHAT IS NEW? In a large population of elderly NSTEACS patients, we observed that women had a short-term outcome similar to that in men and a better 1-year clinical outcome. Revascularization in women was associated with markedly lower early and late mortality.
WHAT IS NEXT? Elderly women with an NSTEACS should receive the same diagnostic and therapeutic approach as men.
Dr. Sbarzaglia is currently affiliated with the Maria Cecilia Hospital-GVM Care & Research, Cotignola, Italy.
The Italian Elderly ACS study was funded by the Italian Society for Invasive Cardiology. Dr. Savonitto is on the advisory board of Eli Lilly, Daiichi Sankyo, and Correvio; and has received research grants from Novartis. Dr. Petronio is a proctor for Medtronic; and a consultant for Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- confidence interval
- hazard ratio
- myocardial infarction
- non–ST-segment elevation acute coronary syndrome(s)
- non–ST-segment elevation myocardial infarction
- percutaneous coronary intervention
- randomized controlled trial
- Received August 18, 2014.
- Revision received December 16, 2014.
- Accepted December 18, 2014.
- American College of Cardiology Foundation
- Lagerqvist B.,
- Säfström K.,
- Ståhle E.,
- Wallentin L.,
- Swahn E.,
- FRISC II Study Group Investigators
- Swahn E.,
- Alfredsson J.,
- Afzal R.,
- et al.
- Damman P.,
- Clayton T.,
- Wallentin L.,
- et al.
- Savonitto S.,
- Cavallini C.,
- Petronio A.S.,
- et al.
- Bueno H.,
- Betriu A.,
- Heras M.,
- et al.
- Otten A.M.,
- Maas A.H.,
- Ottervanger J.P.,
- et al.
- Kaul P.,
- Tanguay J.F.,
- Newby L.K.,
- et al.
- Ahmed B.,
- Piper W.D.,
- Malenka D.,
- et al.
- Malkin C.J.,
- Prakash R.,
- Chew D.P.