Gender differences in outcomes following isolated coronary artery bypass grafting: long-term results

The impact of female gender on clinical outcomes after isolated coronary artery bypass grafting (CABG) has been reported in several studies, with controversial and not definitive results [1–19].

Post-operative outcomes in women undergoing isolated CABG have been intensively studied, due to higher post-operative mortality and morbidity observed in this group of patients [2, 4, 6–12, 14, 15, 17, 18]. However, other studies have shown no difference between male and female patients [1, 3, 5, 13, 16, 19, 20].

Female gender has been clearly reported as an independent predictor of poor post-operative outcomes including mortality after CABG only in a few studies [2, 4, 14, 15]. Moreover, the evidence for the impact of gender in patients who underwent isolated surgical revascularization procedures derives primarily from observational studies based on retrospective registries [3 20], predominantly single center series [1, 4–8, 10–14, 16, 17, 19, 20]. Only few studies investigated a relatively large study population [1, 2, 5, 6, 9, 13, 15, 18] and, with the exception of a few [3–5, 8, 9, 18], most of these studies reported only perioperative or intermediate follow-up outcomes. Finally, another limitation of the previous literature is that it frequently evaluated only the mortality as primary endpoint [6, 8, 10, 11, 13, 15, 17]. There has been less research into long-term differences of other morbidity endpoints and nonfatal events between males and females after isolated CABG [3–5, 9, 18].

Therefore the primary end-point of this multicenter registry study was to evaluate the impact of gender on several outcomes after isolated CABG, comparing 5-year rates of overall death, cardiac related death, myocardial infarction (MI), stroke, postoperative renal failure, overall re-hospitalization, repeat revascularization with CABG or percutaneous coronary intervention (PCI), new pacemaker implantation, new occurrence of heart failure, and need for hospital long-term care in a large study population.

The secondary aim was to evaluate significant risk factors for mortality in this cohort of patients after isolated CABG with multivariate analysis.

A constant reduction in the number of overall isolated elective CABG was observed in our registry between 2003 and 2013, although this reduction occurred mainly in the male patients subgroup (Fig. 1).

The entire male group received 3.1 ± 1.1 bypass grafts, compared with 2.8 ± 1.0 in the female group (p < 0.0001). Left internal mammary artery (LIMA) was used in 92.3 % of the entire male group versus 88.6 % of females (p = 0.0002). Coronary revascularization completely performed with arterial grafts was reported in 23 % of males and 22.6 % of females (p = 0.602). The median duration of follow-up in the entire study cohort was 95.4 ± 39.6 months in the male subgroup and 97.6 ± 39.5 months in the female subgroup.

Kaplan Meier risk curves for the matched population at five years were reported. Both groups reported similar cumulative rates of all-cause death (Fig. 2a) and cardiac-related mortality at five years (Fig. 2b). Females experienced a significantly higher rate of MI (Fig. 3a), and similar occurrence of stroke (Fig. 3b) in the follow-up. No differences were found for new occurrence of postoperative renal failure between groups (Fig. 3c), whereas males experienced a significantly higher cumulative rate of re-hospitalization for cardiac causes (Fig. 4a). The female group confirmed greater occurrence of heart failure episodes at five years (Fig. 4b), and greater need for hospital long-term care, although without any statistical significance (Fig. 4c). No difference was found either for repeat PCI (Fig. 5a), or for RE-DO CABG (Fig. 5b), whereas males reported a higher rate of definitive pacemaker implantation (Fig. 5c).

Multivariate analysis showed the following significant independent predictors of mortality at 5 years: age 70–80 year (HR 1.8, LCI 1.4, UCI 2.1, p < 0.0001), age >80 year (HR 2.5, LCI 1.9, UCI 3.4, p < 0.0001), chronic pulmonary disease (HR 1.4, LCI 1.0, UCI 1.9, p = 0.03), serum creatinine level > =2 mg/dl (HR 2.2, LCI 1.4, UCI 3.3, p = 0.0002), LVEF 30-50 % (HR 1.4, LCI 1.1, UCI 1.6, p = 0.0005), and diabetes (HR 1.6, LCI 1.3, UCI 1.8, p < 0.0001). Female gender was not an independent predictor of death at long-term follow-up.

The impact of gender on clinical outcomes after CABG remains controversial, and because there are many discrepancies between studies [1–20], requires further review.

The main findings of this study are that, after propensity matching, males group received significantly more bypass grafts than the matched females group. LIMA was used in a similar percentage of patients in both genders and total arterial revascularization was performed in similar numbers in both matched cohorts. At five years, both groups reported similar cumulative rate of all-cause death and cardiac-related mortality. Females experienced a significantly higher rate of MI, and similar occurrence of stroke in the follow-up. No differences were found for new occurrence of postoperative renal failure between groups. In particular, no difference was found neither for repeat PCI, nor for RE-DO CABG, whereas males reported a higher need for new pacemaker implantation. Males experienced a significantly higher cumulative rate of re-hospitalization, whereas the female group showed greater occurrence of heart failure episodes at five years and greater need for hospital long-term care, although without any statistical significance. Finally, multivariate analysis of significant predictors of mortality in the overall population failed to demonstrate that female gender was an independent predictor of death at long-term follow-up.

It is widely recognized that women presented more frequently at higher age and with a worse and more complex clinical condition than men [23, 24]. Moreover the smaller body size of women is thought to be related to the smaller diameter epicardial coronary arteries. This, along with a greater preponderance of metabolic syndrome [24], and potential differences in neuro-humoral responses in the vasculature may also contribute to the reported adverse outcomes in the post-operative period.

Several recent reports have confirmed increased post-operative mortality and morbidity in women after isolated CABG [24–27]. A meta-analysis of 20 studies comparing 966,492 patients also reported that women had increased risk for short-term, midterm and long-term mortality compared with men. Mortality remained independently associated with female gender despite propensity score-matched analysis of outcomes [25]. The international randomized controlled IMAGINE study [27] included 2553 consecutive patients (2229 men and 324 women) with a LVEF >40 % who underwent isolated CABG, with the aim to determine sex differences in long-term outcomes. The composite endpoint comprised death, MI, cerebrovascular event, angina, revascularization and congestive heart failure. After adjusting for potential confounders, female sex became a non-significant predictor for prognosis, possibly due to the small sample size of women. The authors concluded that “definite answers regarding sex-differences in long-term outcome after CABG should come from future pooling of studies comprising a larger number of women”.

Our study is one of few large-scale clinical multicenter retrospective studies comparing the long-term mortality, morbidity outcomes and nonfatal events between females and males undergoing isolated CABG. Another strenght point of this study is that, for all 5-year outcomes, with the only exception of stroke, renal failure and redo CABG, the numerosity of the two matched cohorts ensured a good power of the study, ranging from a minimum of 80 %, for all cause death, to a maximum of 99 % in the case of cardiac heart failure.

Like previous studies our entire study cohort also showed significantly different patient risk profiles in the two groups, but multiple factors could explain the differences in our post-operative outcomes compared to other prior reports [24–27]. Close PS matching for example resulted in removal of referral bias and correction of baseline differences. Moreover, this registry presents data from high volume tertiary care referral centers, where surgeons experience and modern post-operative critical care may also partially explain similar outcomes for mortality and several morbidity endpoints between the two genders. In our PS matched population, although the male group received significantly more bypass grafts than the matched female group, widely-used modern techniques such as LIMA grafting and total arterial revascularization were performed in similar numbers in both genders. This strategy may explain the similar overall and cardiac-related mortality rates reported in both groups at five years. It is also likely that the significantly lower total number of grafts performed in females, with a consequent less complete revascularization, explains other worse morbidity outcomes such as higher rates of MI and readmission for heart failure in the female group. Unfortunately, data on graft targets which could be used to verify this inference are not available. Our study also shows that these events occurred significantly in females even though they are less likely to have poor ventricular function preoperatively. This is consistent with the results of other studies reporting that women had similar or improved long-term survival compared with men despite the gender difference in readmission rates for heart failure [5, 28]. Moreover in our study we found that females require hospitalization for long-term care more frequently, consistent with the results of Asch et al. [29]. These authors reported that women are more likely to receive treatment for chronic diseases, but less likely to receive recommended treatments for acute diseases. Our data also confirm the results of Kurlansky et al. [30] who found that, even where optimal grafting practice takes place, women still received fewer grafts than men and experienced a statistically significant higher rate of late myocardial infarction, and that total arterial coronary revascularization in women improved the gender disparity only in terms of mortality outcomes.

Previous studies showed different results in terms of risk of adverse outcomes in women who underwent coronary revascularization with off-pump coronary artery bypass grafting (OPCABG), compared to men. Cartier et al. [8] showed that above 65 years of age men and women had a comparable overall survival (p = 0.7) whereas fewer than 65 women had a lower survival than men (p = 0.001). On the other hand, Puskas et al. [9] compared in-hospital major adverse cardiac events (MACE) and long-term survival after OPCABG vs on-pump CABG. Women disproportionately benefited from OPCABG in operative mortality (p = 0.04). Odds of death for women on CPB were higher than for women treated with OPCABG (OR, 2.07, p = 0.005). However, during the 10-year follow-up, OPCABG and on-pump CABG result in similar survival, regardless of gender. Uva et al. [10] reported that female gender was not an independent risk factor for mortality or major morbidity in an unselected patient population undergoing OPCABG. In our experience there were no significant differences in the percentage of off-pump operations between males and females in the initial unmatched study population. Moreover off-pump technique did not demonstrate significant statistical differences in terms of mortality between matched cohorts. Probably the small size of this matched subgroups did not allow for significant conclusions. Finally off-pump technique had already been included as a covariate in the multivariate analysis, but it did not result an independent risk or protective factor (HR 1.1 p = 0.364).

Although there are conflicting results about gender differences in stroke rate after CABG [5, 24], post-operative stroke has not traditionally been related to gender, and this is also confirmed in our matched analysis. However, at 5 years the evaluation of the effect-size of stroke rate between both cohorts showed an evident lack of statistical power and a consequent uncorrect evaluation of this outcome.

In our study males experienced significantly higher permanent pacemaker implantation in the follow-up. A possible explanation is that men presented with a more complex and diffuse coronary artery disease, and in fact it has been reported that specific severe distribution of coronary lesions is closely correlated with conduction defects [31]. Moreover, Yesil et al. reported that coronary revascularization, even when completely performed, as in the majority of our male subgroup, has little, if any, impact on reversibility of conduction defects [31].

The limitations of a retrospective registry study should be noted. The entire study cohort showed significantly different patient risk profiles in the two groups. Although we tried to rigorously adjust selection bias using propensity score-based analysis, unmeasured confounders and hidden biases may have affected our results. Moreover at 5 years the lack of statistical power of some variables as stroke, renal failure and redo CABG did not ensure a correct evaluation of these outcomes. Finally limitations of the present study include lack of echocardiographic follow-up, graft-patency, cause-of-death data and quality-of-life measures. These parameters could have differed between women and men.

The present study highlights the finding that, despite equivalent overall and cardiac related mortality for both genders after CABG surgery, MI incidence and occurrence of heart failure for women are higher than for men. There are operative disparities in the number of bypass grafts that women receive, which results in a lower percentage of complete revascularization and which could partially explain these differences in morbidity. The similar rates of use of LIMA and total arterial coronary revascularization in both genders is probably a protective factor only in terms of mortality outcomes. Female gender was not found to be an independent adverse risk factor for mortality associated with CABG.

Given the associated conditions in women, we need to ensure future efforts to maximize the completeness of revascularization and the prevention of follow-up morbidity in order to optimize women’s postoperative outcomes to rates observed for men. On the basis of our data, decisions regarding surgical revascularization should not be based on gender.