The association between sex and mortality among patients with cardiovascular disease has been a major topic of study over the past several decades. Despite the increased attention, this relationship is poorly understood. Some studies demonstrate increased rates of mortality among women, some report no difference, and others show lower rates of mortality for women compared with men3-12, 15, 16
. By pooling data from 11 clinical trials, we enhanced our ability to evaluate relationships among sex, clinical characteristics, disease presentation, coronary anatomy, and all-cause mortality following ACS.
In the resulting large patient population, 30-day mortality were higher for women than men, however, much of this difference was attenuated following adjustment for baseline differences. In addition to those clinical parameters included in the adjusted model, differences in a number of variables were identified which could affect the relationship between mortality and sex. These include additional comorbidities, disease presentation, and coronary anatomy.
Consistent with previous findings3, 22, 38, 39
, we found that women as a group were older with more comorbidities than men, including hypertension, hyperlipidemia, diabetes and heart failure. In contrast, men were more likely to be smokers and to have a history of myocardial infarction or bypass surgery. Further, these differences in risk burden were present and similar across all forms of ACS. In particular, the median age of women was similar across the 3 major categories of ACS, although differences between men and women were less in UA than in STEMI.
The reduction in the magnitude of differences in outcomes after multivariable adjustment is consistent with the older age and worse baseline risk factors for women than men. In unadjusted analyses we found almost a 2-fold increased risk for 30-day mortality in women compared with men (OR 1.91, 95% CI 1.83–2.00). A subset of covariates was identified as primary confounders (age, smoking, hypertension, heart rate and height) which had the largest impact on the sex-specific differences. When we fit an adjusted model with only these covariates we get similar results to the fully adjusted model (OR 1.05, 95% CI 0.98–1.13).
Previous analyses demonstrated that certain risk factors, such as age and diabetes confer a different mortality risk in women compared with men13, 14, 18-20, 40
. Data from NRMI found an increased short-term mortality risk for young women compared with young men, with no mortality difference in the older population14
. However, in the current analysis no significant interaction was detected between sex and age (P=0.681) in the overall population. Other studies have found that diabetes is associated with a greater mortality risk among women than men18, 19
. However, in our study the differences in mortality between diabetics and non-diabetics were similar for women and men across the spectrum of ACS, and no significant interaction was detected between sex and diabetes (P=0.118). Differences in inclusion criteria, study design, or endpoint analyzed may partially explain the differences between studies.
Perhaps the most striking findings in our analyses relate to the examination of mortality according to type of ACS. We found a significant interaction between sex and type of ACS (P<0.001) such that 30-day mortality risk among women was higher than men only for those presenting with STEMI. In NSTEMI and UA, women had a lower adjusted 30-day mortality risk than men. These results are in part consistent with prior studies that noted decreased risk of adverse events following UA among women compared with men.4, 22
In the present study we extended these findings to evaluate the relationship between type of myocardial infarction and mortality by sex, demonstrating that women with STEMI have higher mortality than men with STEMI. Thus, there is a gradient of differential risk between the sexes in relation to clinical syndrome. Although many sex-specific studies lump all patients with ACS together and we present these data for purposes of comparability, our study indicates that STEMI, NSTEMI and UA should not be combined, but evaluated separately.
Several potential explanations for sex-related differences in mortality following ACS are offered. Consistent with prior studies and clinical experience, our results indicate that women and men who present with ACS are a heterogeneous group. Studies of low-risk patients have consistently found either no significant difference in the mortality rate between women and men or a lower rate among women4, 5, 12, 41
. In contrast, studies of women at higher risk note similar or increased risk compared with men6, 9, 16
. In our study, we compared 30-day mortality stratified by type of ACS, a design that enabled us to more precisely define the risk in each clinical population independently; therefore, to more appropriately determine the outcome by category of risk. While our data set cannot address a possible contribution from differential effectiveness or safety of therapies, our findings indicate that careful attention to clinical syndrome, clinical characteristics and coronary anatomy are essential to ascertaining and understanding sex related differences.
Alternative explanations for differences in mortality may relate to differences in pathophysiology of ACS according to type of ACS, and by sex. Whereas STEMI is more likely to be caused by acute plaque rupture, NSTEMI/UA often originates from a moderate coronary stenosis42, 43
. It is possible that intrinsic differences in angiogenesis and collateralization between women and men22, 44
play a role, such that a sudden coronary occlusion puts women at greater risk in the setting of STEMI creating more transmural infarcts associated with higher complications. Conversely, in syndromes like NSTEMI/UA without epicardial occlusion, women’s lesser angiographic disease burden is associated with a better prognosis. Sex-based differences in the culprit lesion of acute myocardial infarction also exist45-47
. Plaque rupture is more common in men, yet, plaque erosion is more common in women45
. These basic mechanistic differences may, in part, explain some of the sex-based differences in outcomes following ACS. Unfortunately, ante mortem data such as ours cannot address the differences in anatomic substrate determined post mortem as described above; however, there was no interaction between angiographic disease burden and sex with regard to risk found in our cohort.
It is also possible that the differential risk of death in women following ACS is due to sex-based differences in angiographic disease burden. The relationship between burden of disease and mortality is complex with some studies suggesting worse outcomes in single-vessel coronary disease, perhaps due to less collateral circulation and myocardial preconditioning44, 48-51
. However, the relationship between overall burden of coronary disease and mortality is well established52
. Similar to previous studies8, 21-24
, we observed lower rates of clinically significant coronary stenosis in women compared with men. This finding was consistent across the spectrum of ACS. The apparently paradoxical worse prognosis of women in STEMI, yet better prognosis in UA may represent the complex spectrum of this disease.
Regardless of ACS type, there were no significant differences in 30 day mortality for women and men, after adjusting for clinical covariates and angiographic disease severity and accounting for multiple comparisons. (). Although sex-based difference in outcome may not be completely explained by women’s lesser burden of angiographic disease, coronary anatomy may partially explain the difference in mortality in those with UA, as the adjusted odds ratio for the sex effect was attenuated after the inclusion of angiographic disease severity. Furthermore, our study was unable to detect a significant interaction between sex and angiographic disease severity with respect to 30-day mortality, suggesting a similar effect of anatomy on mortality between women and men.
Strengths and Limitations
The use of a pooled clinical trials database has several advantages53, 54
. First, pooling from several studies allowed us to interrogate a very large sample size, and secondarily to explore coronary angiography findings in a large number of patients. The uniform inclusion and exclusion criteria used for enrollment of both sexes helped to ensure that no systematic biases occurred in diagnosis or sampling between men and women. Similarly, while care in clinical trials may differ from that in the community and may not be generalizable to all men and women presenting with ACS, it is possible that care within a clinical trial setting may be more uniform and therefore more reflective of underlying differences in pathophysiology. Finally, by using patients enrolled in a clinical trial we ensured that all data points were collected independently and carefully monitored.
Our study does have some limitations. As an observational study, we cannot completely exclude residual confounding or selection bias as an alternative explanation of our findings, although we were able to adjust for a wide range of patient characteristics. The database we used merged several clinical trials and inter-trial variability in care may exist that could have influenced results in the pooled patient population. However, only those trials that included both men and women in their study populations were pooled, and adjustment for trial did not change the observed differences in mortality between women and men. Similarly, although the data in our trials were accrued over decades, during which diagnostic standards (e.g.: use of troponins), use of procedures and adjunctive therapies and guidelines adherence all evolved, any relevant changes are likely to have had similar impact on both men and women in each trial. Furthermore, there was no interaction between sex and trial which would have been expected if such temporal changes influenced the results. Additionally, since all patients in this analysis were part of a clinical trial for ACS, we were unable to address the possibility of a differential attrition rate in the pre-hospital phase by sex. Since catheterization was not mandated as part of the trials’ protocols, patient selection may have introduced potential referral bias and survival bias, and therefore should be interpreted with caution. Some variables of interest (e.g. creatinine clearance) were not available in all trials and therefore were unable to explore their relationship with sex and mortality. Nevertheless, the final adjusted model had a C-index of 0.81, indicating excellent discriminatory ability for 30-day mortality. Finally, this was an observational study with complex interactions, thus even a large database may not be definitive without replication.