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Ann Thorac Surg 2000;70:800-805
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

The influence of gender on the outcome of coronary artery bypass surgery

^a Division of Cardiovascular Surgery, Sunnybrook and Women’s College Health Sciences Center, University of Toronto, Toronto, Ontario, Canada

Address reprint requests to Dr Fremes, Division of Cardiovascular Surgery, Sunnybrook and Women’s College Health Sciences Center, 2075 Bayview Ave, Suite H405 Toronto, ON, M4N 3M5, Canada
e-mail: stephen.fremes{at}swchsc.on.ca

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. To assess the impact of gender as an independent risk factor for early and late morbidity and mortality following coronary artery bypass surgery.

Methods. Perioperative and long-term data on all 4,823 patients undergoing isolated coronary bypass operations from November 1989 to July 1998 were analyzed. Of these patients, 932 (19.3%) were females.

Results. During the years 1989 to 1998 there was a progressive increase in the percentage of women undergoing coronary artery bypass surgery. The following preoperative risk factors were more prevalent among women than men: age above 70, angina class 3 or 4, urgent operation, preoperative intraaortic balloon pump usage, congestive heart failure, previous percutaneous transluminal coronary angioplasty, diabetes, hypertension, and peripheral vascular disease (all p < 0.05). Men were more likely to have an ejection fraction less than 35%, three-vessel disease, repeat operations, and a recent history of smoking. Women had a statistically significant smaller mean body surface area than men (1.72 ± 0.18 versus 1.96% ± 0.26% m²).

On average, women had fewer bypass grafts constructed than men (2.9% ± 0.8% versus 3.2% ± 0.9%) and were less likely to have internal mammary artery grafting (76.2% versus 86.1%), multiple arterial conduits (10.1% versus 19.8%), or coronary endarterectomy performed (4.9% versus 8.6%).

The early mortality rate in women was 2.7% versus 1.8% in men (p = 0.09). Women were more prone to perioperative myocardial infarction (4.5% versus 3.1% p < 0.05). After adjustment for other risk variables, female gender was not an independent predictor of early mortality but was a weak independent predictor for the prespecified composite endpoint of death, perioperative myocardial infarction, intraaortic balloon counterpulsation pump insertion, or stroke (8.55 versus 5.9%; odds ratio, 1.30; 95% confidence interval, 0.99 to 1.68; p = 0.05)

Recurrent angina class 3 or 4 was more frequent in female patients (15.2% ± 4.0% versus 8.5% ± 2.0% at 60 months, p = 0.001) but not repeat revascularization procedures (percutaneous transluminal coronary angioplasty, redo) (0.6% ± 0.3% versus 4.1% ± 0.8% at 60 months). Actuarial survival at 60 months was greater in women then men (93.1% ± 1.7% versus 90.0% ± 1.0%), and after adjustment for other risk variables, female gender was protective for late survival (risk ratio, 0.40; 95% confidence interval, 0.16–0.74; p < 0.005).

Conclusions. Perioperative complications were increased and recurrent angina more frequent in women. Despite this, late survival was increased in women compared with men after adjustment for other risk variables

	Introduction

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There is a great uncertainty regarding the impact of gender as an independent risk factor for morbidity and mortality following coronary artery bypass surgery. Most studies show that women have a higher risk for morbidity and mortality following coronary artery bypass grafting (CABG) procedures than do their male counterparts [1–6]. One of the key problems, however, in attempting to compare outcomes between genders is a difference in the preoperative clinical characteristics of men and women. Smaller body surface area and smaller coronary arteries could also lead to reduced graft patency rates [2–3]. Other investigators have documented an underutilization of noninvasive and invasive testing in women compared with men that may influence perioperative results [7].

Another debatable issue is long-term results after revascularization in women. In contrast to most results, the recent Bypass Angioplasty Revascularization Investigation (BARI) study [8] demonstrates better long-term survival in women who have undergone revascularization techniques. This study was performed on selected patients who were amenable both to percutaneous transluminal coronary angioplasty and CABG revascularization; the extent we can generalize from the findings is therefore uncertain. In the current study, we have used an extensive database containing 180 different variables to describe each patient as well as a long-term follow-up of up to 9 years to determine the short-term and long-term results in unselected patients.

	Material and methods

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Study population
The cardiac surgical unit of Sunnybrook and Women’s College Health Science Center of the University of Toronto opened November 27, 1989. Between November 27, 1989, and July 31, 1998, 4823 patients underwent coronary revascularization as an isolated procedure. Of those, 932 (19.3%) were women. Data were collected prospectively and entered into a computerized database.

Surgical procedure: anesthetic and operative techniques
Low-dose fentanyl citrate (10 to 15 µg/kg), midazolam (2 to 3 mg), isoflurane (0.5 to 2%), and propofol (100 to 150 µg · kg^-1 · min^-1) were used for induction and maintenance of anesthesia. Standard median sternotomy and aorta–right atrial cannulation were performed for cardiopulmonary bypass. Patients were either cooled to 28°C (earlier in the study) or remained normothermic (32 to 37°C) [9]. Revascularization was performed during a single aortic cross-clamp and cardioplegic arrest, in most instances. Blood cardioplegic solution was delivered in a 4:1 ratio before 1996 and an 8:1 ratio after that time [10, 11]. Cold cardioplegia (10°C) was utilized in the early years of the study, while warm or tepid (33°C) cardioplegia was used more frequently in later years [9–11]. Blood cardioplegic solution was delivered either antegrade, by way of the aortic root and completed vein grafts, or retrograde, through the coronary sinus. After cardioplegic solution induction, additional doses of 300 to 500 mL were administered after completion of each distal and proximal anastomoses.

Long-term follow-up
Follow-up information was obtained on 4460 patients (92.5% of late survivors) by repeat patient visits, contact with the patient’s physician, or response to a patient questionnaire. Mean follow-up was 22 ± 20 months.

Study endpoints
The prespecified outcomes of interest to the investigators were early mortality (< 30 days postoperatively) and cardiovascular morbidity (perioperative myocardial infarction (MI), perioperative low output syndrome necessitating intraaortic balloon counterpulsation pump usage, and perioperative cerebrovascular accident). Follow-up endpoints included late mortality, late MI, repeat interventions (redo CABG, PTCA) and Canadian Cardiovascular Society angina class 3 or 4.

Statistical analysis
Statistical analysis was facilitated with SAS for PC software (SAS Institute, Cary, NC) [12]. Clinical and catheterization features were analyzed by descriptive statistical methods. Continuous variables were compared by Student’s t test, and categorical variables were compared using ² or Fischer’s exact test analysis.

Logistic multiple regression analysis using the maximum likelihood estimates was employed to determine independent predictors of operative mortality and early nonfatal complications. Model discrimination was evaluated by the area under the receiver operator characteristic curve [13], and the calibration was assessed with the Hosmer-Lemeshow goodness-of-fit test [14]. To determine the effect of gender across the risk spectrum, the predicted mortality and morbidity and mortality were calculated for each patient according to the logistic coefficients (excluding gender) and ranked into quintiles. Actual results were then compared between men and women by risk quintile and analyzed by Fischer’s exact test.

Actuarial techniques using the life-table method were employed to assess late events. Survival curves were compared between groups by the log rank method and multivariate analysis by the Cox proportional hazards method. A p value is depicted for each comparison.

	Results

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Demographics and preoperative risk factors
During the years 1989 to 1998 there was a progressive increase in the percentage of women undergoing CABG (Fig 1). A comparison of risk factors for women and men shows that there were statistically significant differences in the two populations (Table 1). Women were older and a larger percent of them were older than 70 years (Fig 2). The female population had a greater prevalence of Canadian Cardiovascular Society angina class 3 or 4, needed more urgent surgery, and required preoperative intraaortic balloon counterpulsation pump insertion more often than men. Women were more likely to have congestive heart failure preoperatively and had greater incidence of prior PTCA. Comorbidities such as diabetes mellitus, hypertension, and peripheral vascular disease or carotid artery stenosis were significantly more prevalent among women. Women had a statistically significant smaller body surface area than men (Fig 3). There was no difference in body mass index (p = 0.34), although the distribution of values was broader in women than in men. Men, on the other hand, were more likely to have an ejection fraction of less than 35%, three-vessel disease, redo operations, and a recent history of smoking.

View larger version (16K): [in this window] [in a new window]   Fig 1. Percentage of female patients undergoing CABG surgery, expressed as a percentage of total CABG cases per year. Over the past decade, the relative number of women undergoing the procedure has increase progressively. (CABG = coronary artery bypass graft)

View larger version (15K): [in this window] [in a new window]   Fig 2. Percentage of male or female patients older then 70 years undergoing CABG. For each of the later years of the study, approximately 35% of female patients were elderly, compared with less then 25% of men. (CABG, coronary artery bypass graft)

View larger version (17K): [in this window] [in a new window]   Fig 3. Comparison of female and male study patients’ body surface area. Female patients were significantly smaller then male patients, according to body surface area calculations.

Early results
Perioperative results are summarized in Table 2. Early mortality (2.7%, versus 1.8% p = 0.09) and perioperative MI (4.5% versus 3.1% p < 0.05) occurred more frequently in female than male patients. The cluster of early mortality and cardiovascular complications was significantly more common in women (p < 0.01). The incidences of low output syndrome (15.8% versus 10.9% p < 0.001), ventilation for greater than 24 hours (6.0% versus 4.5% p = 0.06), and sternal wound infections (2.8% versus 1.7% p < 0.05) were increased in women. Women were more likely to require transfusion of any blood product; 90.5% underwent transfusion, compared with only 46.6% of men (p < 0.001). Transfusion of homologous red cells was required in 89.8% of women (2.7 ± 2.6 U) compared with 43.0% of men (1.2 ± 2.4 U). Chest reopening for bleeding was performed in 1.5% of women and 1.9% of men. Though the intensive care unit stay was not significantly different between women and men (45.5 ± 72.7 versus 42.8 ± 77.6 hours), the postoperative stay was significantly longer for women (7.5 ± 7.0 versus 6.8 ± 6.5 days).

View larger version (15K): [in this window] [in a new window]   Fig 4. Recurrent angina, depicted in an actuarial manner, was more frequent in the female than in the male cohort.

View larger version (14K): [in this window] [in a new window]   Fig 5. Actuarial survival of female patients was nonsignificantly greater than male patients 5 years postoperatively. Both early and late deaths were included in the calculations.

View larger version (16K): [in this window] [in a new window]   Fig 6. Freedom from death or myocardial infarction (including early and late death or myocardial infarction) was nonsignificantly greater in men at 5 years following surgery.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Our study, supporting previous reports, has shown that women have a greater prevalence of most risk factors (old age, Canadian Cardiovascular Society angina class 3 to 4, urgent operation, congestive heart failure, prior PTCA, diabetes mellitus, hypertension, peripheral vascular disease, and small body surface area). Men have higher prevalence of left ventricular ejection fraction of less than 35%, triple vessel disease, and history of smoking [6]. We also found that internal mammary artery grafts and multiple arterial grafts were less frequently used in women [6].

Operative mortality in CABG is generally greater in women than in men [1–6]. According to the Society of Thoracic Surgeons (STS) database (344,914 patients operated upon between 1994 and 1996), the operative mortality rate in women is 4.52% versus 2.61% in men [6]. The STS database study showed that operative mortality was greater in women in 31 individual stratified analyses. According to multivariate analysis, female gender was found to be an independent risk factor for mortality in low-risk and medium-risk patients groups [1], whereas female gender had a greater influence in the medium- and high-risk quintiles according to our analysis.

The unadjusted morbidity (8.4% versus 5.9%) and mortality (2.7% versus 1.8%) in our institution were higher in women than in men (Table 2). Female gender was not an independent risk factor for early mortality and only a weak independent predictor for the combined endpoint of early mortality and cardiovascular morbidity. We concluded that within this study, the differences in risk factor profile between men and women assumed greater significance than female gender itself. The Working Group Panel on the Collaborative CABG Database Project considers female gender as one of seven core variables related to operative mortality [5]. Female gender is considered a risk factor for operative mortality in the province of Ontario, with an adjusted odds ratio of 1.68 [4] that is similar to the crude odds ratio of the STS investigation (1.77 [6]).

Previous studies have shown better long-term results after surgery in men. Men have experienced greater relief of angina [15, 16] and higher graft patency rates [15, 16]and have had fewer complaints of congestive heart failure and functional disability [17]. Despite less symptom relief and lower graft patency rates, long-term survival data revealed no significant differences between sexes after CABG. A secondary analysis of the BARI study showed similar early mortality rates after CABG in women and men but surprisingly, better late survival and freedom from MI in women than men after adjustment for other risk variables [8]. The BARI study was performed in a selected group of patients (those who were amenable for both CABG and percutaneous coronary angioplasty).

At Sunnybrook, late survival was higher in women 4 and 5 years postoperatively and female gender was protective according to the Cox proportional hazards model. Life expectancy is greater in women then men in Western countries. Could the survival advantage seen in the female surgical patients be related to this known difference in life expectancy? Reasons for the increased life expectancy in women are probably associated with differences in the prevalence of multiple health-related covariates common to both men and women plus some gender-specific effects. It should be emphasized that one of the key differences between men and women is the later onset of coronary artery disease in women. By extrapolation, after controlling for age, female surgical patients may have a shorter duration of coronary artery disease, which presumably would be associated with increased longevity.

Female patients were more likely to have postoperative angina, as well as MI, but less likely to have repeat intervention than men. Incomplete revascularization, graft occlusion, and progression of coronary disease all contribute to postoperative angina. Factors characteristic of female operative patients—such as small coronary size, fewer bypass grafts, and underutilization of the left internal mammary, in association with less multivessel disease and better ventricular function at the time of the original operation—may be associated with a greater incidence of postoperative angina. On the other hand, the smaller coronary arteries of women may be less suitable for repeat revascularization, and advanced age may mitigate against repeat CABG.

Estrogen replacement therapy after menopause has been shown to be protective against development of coronary artery disease in observational studies [18, 19]. The Heart and Estrogen/progestin Replacement Study (HERS) investigators [20] found no overall benefit from hormone replacement but in fact noted increased cardiovascular events in the first year of therapy, although they did observe a possible reduction in events with extended therapy. These results suggest that starting hormone replacement therapy perioperatively may be hazardous; the long-term use of hormone replacement could, however, limit perioperative complications, enhance late results, or both.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The authors express their appreciation to Ms Tarja Antila for assistance in preparation of the manuscript.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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