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(Circulation. 1995;92:80-84.)
© 1995 American Heart Association, Inc.

Articles

Is Sex a Factor in Determining Operative Risk for Aortocoronary Bypass Graft Surgery?

Lynda L. Mickleborough, MD; Yasushi Takagi, MD; Hiroshi Maruyama, MD; Zhao Sun, MA; Shanas Mohamed, RN

From the Division of Cardiovascular Surgery, Department of Surgery, University of Toronto and the Toronto Hospital (Ontario), Canada.

Correspondence to Dr L. Mickleborough, EN 13-217, The Toronto Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4.

	Abstract

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Background This study examines trends and sex differences in characteristics of patients referred for bypass graft surgery to identify factors associated with operative morbidity and mortality.

Methods and Results Data were collected prospectively on consecutive patients (1132 men and 355 women). Over time, the proportion of patients >65 years old, with diabetes, or requiring urgent surgery, increased. Predictors of mortality were age >75 years, urgent surgery, and poor left ventricular (LV) grade. Women were older (62±9 versus 59±9 years, P<.001) and had more varicose veins (18% versus 7%, P<.001), diabetes (27% versus 18%, P<.001), hypertension (48% versus 41%, P<.05), peripheral vascular disease (16% versus 12%, P<.05), and more severe angina (P<.001). There were no sex differences in prior myocardial infarction (59% versus 62%) or need for urgent surgery (17% versus 18%). Women had a higher ejection fraction (51%±12% versus 47%±14%, P<.001) and fewer diseased vessels (2.4±0.7 versus 2.6±0.6, P<.001) and received fewer grafts (2.9±0.9 versus 3.3±0.8, P<.001). Women had smaller body size but were no more likely to have small target vessels (<1.5 mm). There was no sex difference in operative mortality (1.4% versus 1.1%), perioperative myocardial infarction (4.8% versus 3.5%), need for intra-aortic balloon pump (10% versus 8%), stroke (1.7% versus 1.4%), reexploration for bleeding (1.7% versus 1.7%), or leg infection (2.0% versus 1.4%). Women had fewer sternal wound infections (0.6% versus 2.2%, P<.05).

Conclusions Predictors of mortality include advanced age, decreased LV function, and need for urgent surgery. With time, despite increasing age, associated diabetes, and increased urgent surgery, operative mortality has decreased. Women were older and had more diabetes and hypertension but less extensive disease and better LV function. Bypass graft surgery was associated with equally low mortality in women and men (1.4% versus 1.1%). Concern over increased operative mortality in women should not bias referral patterns for angiography and coronary bypass graft surgery.

Key Words: sex • bypass • mortality • vessels

	Introduction

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In recent years, because of improvements in medical treatment and trends in angioplasty for coronary artery disease, referral patterns for coronary artery bypass graft surgery have shifted, with an increasing number of "high-risk" patients being referred for surgery.^{1 2} In most reported series, there has been a large preponderance of male patients. Risk factors for coronary artery bypass graft surgery may be different depending on sex. In the past, female sex, in itself, has been considered a risk factor for coronary artery bypass graft surgery.^{3 4 5 6 7 8 9 10} This may in part have led to the bias that appears to exist against referral of women for angiography or bypass surgery.^{11 12 13 14} In several recent surgical series, however, the difference in the operative mortality between men and women has decreased. In some reports, the residual difference has been explained by sex-related variation in comorbid factors and difference in body size.^{5 15 16} The present study was undertaken to examine trends in clinical characteristics in patients referred for bypass graft surgery over an 11-year period, to identify factors associated with increased operative mortality, and to determine whether sex differences exist in clinical characteristics, morbidity, and mortality.

	Methods

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Between January 1982 and March 1993 (11 years and 2 months), data were collected prospectively on 1487 consecutive patients undergoing isolated coronary artery bypass graft surgery by one surgeon at the Toronto Hospital. The hospital records of each patient were reviewed by trained chart reviewers using a standard data collection form.

Clinical Presentation
Preoperative clinical variables were prospectively gathered and evaluated, including sex, age, history of prior myocardial infarction, anginal pattern, diabetes, height, weight, body surface area calculated by the Du Bois formula,¹⁷ obesity (defined as body mass index >27 calculated by method of Quetelet),¹⁸ smoking history, hypertension, family history of coronary artery disease, peripheral vascular disease, varicose veins, symptom class, and timing of surgery. Anginal classification included stable or unstable (pain for >20 minutes, usually accompanied by transient ECG changes or with evidence of acute infarction). Timing of operation was designated as elective or urgent (from the coronary care unit or catheterization laboratory with an acutely unstable patient).

Catheterization Data
Cardiac catheterization was performed in all patients to assess ventricular function and the extent of coronary artery disease. The left ventricular (LV) ejection fraction was estimated by a single-plane ventriculogram and graded on a scale of 1 to 4 (1, >60%; 2, >40% to 60%; 3, >20% to 40%; and 4, <20%). Coronary narrowing of 50% was considered significant. Factors derived from cardiac catheterization and collected on each patient included the number of diseased vessels, LV grade, and ejection fraction.

Intraoperative and Postoperative Data and Operative Techniques
Fentanyl citrate was used for induction and maintenance of anesthesia. Cardioplegia techniques have changed with time. In 1982, multidose cold crystalloid cardioplegia was used. Since 1984, cold blood cardioplegia has been used, and in 1985, a terminal "hot shot" was introduced.¹⁹ During the entire series, myocardial temperatures in three major vascular distributions were measured after the initial dose of cardioplegia. In cases with uneven cooling (regional temperature >18°C), grafts have been constructed first to the warmest area (diagonal in the case of left anterior descending coronary artery occlusion and left internal mammary artery graft), and if needed, additional doses of cardioplegia were given down the completed graft to achieve uniform cooling.²⁰ Between 1982 and 1987, we used systemic hypothermia (25°C). Since 1987, temperature has been allowed to drift and usually falls to 32°C during the cross-clamp period. No topical cooling was used in this series.

Since 1984, use of the internal mammary artery has increased dramatically. In this series, reasons for not using the internal mammary artery included poor quality of sternal bone as assessed at the time of sternotomy, small size or inadequate flow in the pedicle after harvesting, a history of chronic systemic steroid therapy, or previous chest wall irradiation. Proximal vein anastomoses have been performed during a single period of cross-clamping. Coronary luminal diameter at the site of each distal anastomosis has been assessed with graduated probes to determine whether the distal vessel was 1.5 mm or <1.5 mm in diameter. Information obtained from the operating room note included number of grafts performed, number of endarterectomies, number of vessels <1.5 mm in diameter, pump time, and cross-clamp time.

Postoperative Care and Outcome
Postoperative mortality and morbidity were recorded prospectively. Operative mortality was defined as a death within 30 days of operation or during hospital stay. Preoperative and postoperative ECGs were reviewed by a cardiologist who was not involved with the clinical care of the patient. A perioperative myocardial infarction was defined as the appearance of new Q waves on ECG or an elevation in creatine kinase (CK) enzyme, with CKMB >50 U/L or >8% of the total CK when the ECG revealed a left bundle branch pattern or inadequate R-wave progression.¹⁵ A postoperative stroke was diagnosed if a persistent neurological deficit was present at the time of discharge. Sternal wound infection was diagnosed if prolonged hospitalization was required because of antibiotic therapy or sternal rewiring. Leg infection was diagnosed if prolonged hospitalization was required because of antibiotic therapy or wound dressing changes. In patients with distal vessels <1.5 mm in diameter, intravenous nitroglycerin infusion was used prophylactically and was switched to nifedipine when patients were taking oral medications.

Statistical Analysis
The SAS (SAS Inc) and BMDP (BMDP Software) programs were used for statistical analysis. Predictors of operative mortality were determined by univariate and multivariate techniques. For the univariate analysis, discrete data were analyzed with the ² test or Fisher's exact test where appropriate. Continuous data were evaluated by Student's t test or ANOVA. Statistical significance was assumed at a value of P<.05. Variables that were significant by univariate analysis plus sex were entered into the multivariate analysis by the stepwise logistic regression technique.

Patient Population
The clinical data are shown in Table 1. There were 355 women and 1132 men. The women differed from the men in the following ways. Not surprisingly, the women were smaller (in height, weight, and body surface area) than men; however, a similar proportion of men and women were obese (body mass index >27). Women were older and more likely to have associated diabetes, hypertension, and a positive family history for coronary artery disease. Women were also more likely to have varicose veins and peripheral vascular disease. On the other hand, more men had a previous history of smoking. Women were more symptomatic than their male counterparts (increased Canadian Cardiovascular Society [CCS] angina class); however, in our series, men and women were comparable with respect to history of previous myocardial infarction, presentation with unstable angina, evidence of significant mitral regurgitation, need for preoperative intra-aortic balloon support, or urgent surgery.

View this table: [in this window] [in a new window]   Table 1. Clinical Criteria

Angiographic criteria are listed in Table 2. Men had poorer LV function and more severe coronary artery disease than their female counterparts (P<.001). At surgery, women had fewer grafts (2.9±0.9 versus 3.3±0.8 grafts per patient, P<.001) and were less likely to have an internal mammary artery graft (63.3% versus 75.9%, P<.001). In keeping with the increased number of grafts in male patients, cross-clamp and pump times were significantly longer in men versus women (55±18 versus 49±17 minutes and 105±28 versus 97±29 minutes, respectively, P<.001). Men were more likely to require endarterectomy because of diffuse distal disease (11.2% versus 7.6%), but the trend did not quite reach statistical significance (P=.058). Despite their smaller body size, women were no more likely than men to have a grafted vessel <1.5 mm in diameter (30.9% versus 31.3%), nor were women more likely than men to have a blocked vessel not grafted at surgery because of small size or intramyocardial course (13.8% versus 12.1%).

View this table: [in this window] [in a new window]   Table 2. Angiographic Criteria

	Results

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In our series, operative mortality was not influenced by sex (1.4% for women versus 1.1% for men). The incidences of perioperative myocardial infarction and need for intra-aortic balloon support were similar in the two groups (4.8% versus 3.5% and 10.0% versus 8.1%, respectively). The incidence of stroke and reoperation for bleeding was similar in the two groups (1.7% versus 1.4% and 1.7% versus 1.7%, respectively). The incidence of leg infection was similar for women and men (2.0% versus 1.4%); however, women had a significantly lower incidence of sternal wound infection (0.6% versus 2.2%, P<.05).

Trends in Coronary Artery Bypass Population and Operative Mortality
Over the 11-year period of this study (11 years plus 2 months), the proportion of women versus men undergoing bypass surgery did not change with time (varying from 29% to 35% women in the four time periods of the study). Trends in patient characteristics by sex and operative mortality are depicted in the Figure. There was a statistically significant trend for increasing age (patients >65 years old), increasing diabetes, and increasing need for urgent surgery with time (P<.001). Although there was a trend for increasing percentage of patients with poor LV function (ejection fraction <40%), this trend did not reach statistical significance. There was no change in the extent of coronary artery disease (triple-vessel disease or left main stem stenosis) over the period of the study. Despite increasing risks, the operative mortality decreased during the duration of the study (P<.05).

View larger version (77K): [in this window] [in a new window]   Figure 1. Bar graphs showing changing prevalence of patients with age >65 years, diabetes, urgent operation, left ventricular (LV) ejection fraction <40%, left main (LM) stenosis or triple-vessel disease (3VD), and operative mortality in time periods 1982-1984, 1985-1987, 1988-1990, and 1991-1993. Percent prevalences for both men and women are presented. Solid bars indicate men; hatched bars, women.

Predictors of Operative Mortality
In our series, factors that were related to operative mortality by univariate analysis were age >75 years, peripheral vascular disease, decreased ejection fraction (<40%), and urgent surgery. Sex was not a factor in predicting operative risk. By multivariate stepwise logistic regression analysis, only age >75 years, decreased ejection fraction, and urgent surgery were significant predictors of increased mortality. The predicted operative mortality based on these three risk factors varies from 1% to 17%.

	Discussion

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In published series of coronary bypass graft surgery, a number of clinical and hemodynamic variables have been reported to be associated with increased operative risk. These variables include increased age, need for urgent surgery, comorbid factors such as diabetes as well as indexes of LV function (decreased ejection fraction), and increasing severity of coronary artery disease.^{7 21 22 23} It is not known, however, whether these factors affect surgical mortality to the same extent in men and women. In many series, a higher hospital mortality has been reported after bypass graft surgery in women versus men.^{3 4 5 6 7 8 9 10} In recent studies, some of the excess risk in women has been attributed to comorbid factors (increased diabetes and hypertension) and decreased body size.^{15 16 24}

In general, women referred for bypass surgery have been older and have had a higher incidence of diabetes and hypertension than their male counterparts.^{11 24 25 26 27} Our findings concur with this. Many series report an increased need for urgent surgery in women.^{11 24} We did not find this, although symptoms were more severe in women (83% in CCS angina classes 3 and 4 versus 72% for men, P<.05). A higher incidence of prior myocardial infarction in men has been reported,^{25 27 28} but in our series, the percentages of women and men with a prior myocardial infarction were similar (58.9% versus 61.7%). In our series, coronary artery disease was more severe in men (triple-vessel disease or left main stem stenosis, 66.7% versus 56.8%, P<.001), and LV function was more likely to be compromised (LVEF <40%, 29% versus 21%, P<.001).

In our experience, the characteristics of those referred for bypass graft surgery have changed with time (Figure). In recent years, patients are older, have an increased incidence of diabetes and lower ejection fraction, and require more urgent surgery. This agrees with trends previously reported.^{15 28 29} Despite these trends, operative mortality in our series has decreased with time. This may be attributed to increased surgical experience or improvements in cardioplegia techniques (use of blood versus crystalloid cardioplegia or addition of terminal hot shot).

In our series, the only predictors of operative mortality were age >75 years, decreased ejection fraction <40%, and the need for urgent surgery. In our hands, operative mortality for women was no higher than for men. One can speculate that in women, increased risk associated with advanced age and increased incidence of diabetes was counteracted by decreased risk associated with less diffuse disease and better ventricular function than in their male counterparts. The need for urgent surgery was no different in the two groups.

In the past, increased mortality in women has been blamed on technical difficulties related to small vessel size, which is known to influence graft patency.^{30 31 32 33 34} However, it has been shown that vessels 1.5 mm in diameter do not present a technical challenge and have been associated with good long-term patency.³⁵ Therefore, it may be misleading to look at average vessel size in men and women. We chose to assess the adequacy of distal vessels (1.5 mm) rather than absolute size. There was no difference in the percentage of women versus men with small distal vessels (<1.5 mm) at the time of surgery. In all patients with small distal vessels, we used intravenous nitroglycerin for 24 hours followed by nifedipine therapy in an effort to prevent vessel spasm and graft occlusion. Perhaps this practice has helped to achieve the low perioperative infarction rate (4.8% versus 3.5%) and low operative mortality in both groups (1.4% versus 1.1%).

If results of surgery were examined with respect to body size (small, 1.8 m² versus large, >1.8 m² body surface area), the mortality was the same (1.1% versus 1.0%), but the incidence of perioperative infarction and the need for perioperative intra-aortic balloon support were higher in patients with small body size (5.4% versus 2.6%, P<.05, and 11.4% versus 6.8%, P<.05, respectively).

Use of the internal mammary artery for grafting has been associated with decreased operative mortality in some series.^{36 37} We used fewer mammary arteries in female patients. In most instances, the reason for this was not inadequate size or flow in the harvested pedicle but rather our reluctance to dissect out the mammary artery in older women who had a soft, friable sternum at the time of sternotomy. In these patients, we felt that harvesting the mammary artery might increase the risk of sternal wound infection or dehiscence. In our series, not only did women have a low operative mortality, but they also had a lower risk of sternal wound infection than their male counterparts (0.6% versus 2.2%, P<.05). We believe the low incidence of sternal wound complications in women was a result of our reluctance to use the internal mammary artery in women with poor-quality bone. It has been our impression that tissues in female patients, especially postmenopausal women, are often more friable and difficult to work with than their male counterparts. However, with careful surgical techniques, satisfactory results can be achieved.

Our study confirms that over the past 11 years, patient demographics in those referred for bypass graft surgery are shifting to include more patients with previously identified risk factors such as advanced age, diabetes, and need for urgent surgery. Nevertheless, in our experience, overall mortality for bypass graft surgery has decreased with time. In this series, bypass graft surgery was performed in women with equally low operative mortality as in men, even though women had a higher incidence of comorbid factors, including increased age, diabetes, and hypertension. On the other hand, women referred to us for bypass surgery have less extensive coronary artery disease and better LV function than their male counterparts. Although women were smaller than men, they were no more likely to have distal vessels of less than adequate size (<1.5 mm), and small body size was not a risk factor for operative mortality in this series. Concern over increased operative mortality in women should not bias referral patterns for angiography or coronary bypass graft surgery. More studies are needed with large numbers of female patients to examine sex-specific risk factors for coronary bypass graft surgery.

	Acknowledgments

 
This study was supported in part by a grant from the Heart and Stroke Foundation of Ontario. We extend our appreciation to Hilary Vincent for the excellent preparation of the manuscript.

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