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Ann Thorac Surg 2006;81:1632-1636
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Sex-Specific Long-Term Outcomes After Combined Valve and Coronary Artery Surgery

Torsten Doenst, MD a , b , Joan Ivanov, PhD a , Michael A. Borger, MD, PhD a , Tirone E. David, MD a , Stephanie J. Brister, MD a , *

a Division of Cardiovascular Surgery, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada
b Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany

Accepted for publication November 28, 2005.

* Address correspondence to Dr Brister, Division of Cardiovascular Surgery, Toronto General Hospital, 200 Elizabeth St, EN-14-217, Toronto, ON M5G 2C4, Canada (Email: stephanie.brister{at}uhn.on.ca).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The purpose of this study is to compare sex-specific, long-term outcomes after combined valve and coronary artery bypass graft surgery (CABG).

METHODS: Between 1990 and 2000, 1,567 patients underwent combined valve and CABG surgery at our institution. Our surgical database was linked to a governmental administrative hospital discharge database and a registry of deaths to obtain long-term follow-up. All patients underwent CABG plus aortic (62%), mitral (31%), or multiple valve surgery (7%).

RESULTS: Women had more preoperative risk factors than men (namely, hypertension, diabetes mellitus, congestive heart failure, atrial fibrillation, and stroke; all p < 0.001). The prevalence of triple-vessel disease was the same between men and women, but women received fewer mammary grafts and fewer total bypass grafts (both p < 0.01). Women received fewer mitral valve repairs and more mitral valve replacements than men (p = 0.014). Length of follow-up was 5.3 ± 3.2 years (mean ± SD; range, 0 to 12.5) and was 99.8% complete. Both sexes had similar long-term survival rates. Women were at higher risk of stroke during follow-up (risk ratio = 1.52, 95% confidence interval: 1.1 to 2.1). There were no sex differences in rehospitalization for acute myocardial infarction (p = 0.9), heart failure (p = 0.4), redo cardiac surgery (p = 0.5), or endocarditis (p = 0.4).

CONCLUSIONS: Women have a higher preoperative risk profile than men undergoing combined valve and CABG surgery, but long-term survival rates are similar. Female sex is an independent predictor of stroke during follow-up. Further studies should focus on the cause of increased risk of stroke and methods of prevention.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Over the last decade, growing attention has been paid to the differences in outcome between men and women undergoing cardiac surgery [1–3]. Most of these studies provide comparisons of perioperative and short-term outcomes only [4, 5]. The majority of information regarding sex-specific long-term results after cardiac surgery comes from studies of patients undergoing isolated coronary artery bypass graft surgery (CABG) [6–8]. While many studies have examined differences between men and women undergoing CABG, few have studied patients undergoing valvular procedures [9–11]. It is important to obtain long-term information on combined valve and CABG patients, as these patients represent an increasing proportion of the cardiac surgery population and they are at increased risk of morbidity and mortality [12, 13].

We have previously demonstrated that female sex is an independent risk factor for short-term (namely, perioperative) mortality in patients undergoing combined CABG and valve surgery [14]. The purpose of the current study was to compare long-term cardiovascular morbidity and mortality in men versus women after combined CABG and valvular surgery.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Perioperative data for all patients undergoing cardiac surgery at the Toronto General Hospital were entered prospectively into a database. A total of 1567 consecutive patients undergoing combined CABG and valve surgery between January 1990 and October 2000 were identified. Long-term follow-up was obtained by linking our clinical database to a governmental administrative hospital discharge registry (the Canadian Institute of Health Information database) and to a governmental registry of deaths (Registered Persons Data Base). All analyses were performed at the Institute for Clinical Evaluative Sciences in a secured environment. Closing date for follow-up data was March 31, 2001. The study was approved by our institutional Research Ethics Board.

Preoperative Investigations
Cardiac catheterization was performed in all patients over age 40 years to assess the extent of coronary artery disease. Coronary artery narrowing of more than 50% was considered significant and was treated with coronary bypass grafting. Left ventricular ejection fraction was quantified by echocardiography or single-plane ventriculography and was graded on a scale of 1 to 4 (1, >60%; 2, 40% to 59%; 3, 20% to 39%; and 4, <20%). Extent and location of valvular disease was determined by echocardiography or cardiac catheterization, or both.

Operative Technique
Fentanyl citrate and propofol were used for induction and maintenance of anesthesia. Cardiopulmonary bypass (CPB) was established with mild systemic hypothermia (34 °C). Myocardial protection was achieved using cold, intermittent potassium blood cardioplegia, followed by a terminal "hot shot." The left internal thoracic artery and saphenous veins were used as conduits for bypass grafting. Construction of distal coronary bypass anastomoses was performed first, followed by valve replacement or repair. The proximal coronary bypass anastomoses were performed after closure of the cardiac chambers, under a single aortic crossclamp technique. Pharmacologic or mechanical support was initiated during weaning from CPB as required. All patients were admitted to the intensive care unit postoperatively and then transferred to the ward when their hemodynamic and respiratory functions were stable.

Variables and Outcomes
Preoperative data that were obtained in all patients included age, sex, and associated comorbidities including diabetes mellitus, renal failure, previous cardiac operations, New York Heart Association (NYHA) functional class, Canadian Cardiovascular Society angina class, extent of coronary artery disease, left ventricular ejection fraction, valvular pathology, endocarditis, and cardiac rhythm. Perioperative variables included type and location of valve prosthesis or repair, type of coronary bypass conduit, number and site of coronary bypass grafts, and aortic crossclamp and CPB times.

Long-term outcomes of interest consisted of survival and hospital readmissions for acute myocardial infarction, congestive heart failure, repeat revascularization (by CABG or percutaneous techniques), repeat valve surgery, endocarditis, and stroke. Survival data were determined from the governmental registry of deaths and hospital readmission data were obtained from the governmental administrative hospital discharge registry. The Privacy Act prohibited us from performing subanalyses, which may contain cell sizes of fewer than 5 patients.

Statistical Methods
Continuous variables are reported as mean ± SD in the tables and text, and categorical variables are reported as percentages. Differences in perioperative variables between sexes were assessed with unpaired t tests for continuous variables and {chi}2 or Fisher's exact test for categorical variables. Univariate comparisons of long-term outcomes were performed using the Kaplan-Meier method. The independent predictors of each outcome of interest were determined by Cox regression analysis. The survival curves were constructed directly from the data, and they were compared by the log-rank test. Statistical significance was defined as p less than 0.05. For all statistical analyses, SAS, version 8.2 (SAS Institute, Cary, North Carolina) was used.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Table 1 shows the perioperative clinical variables in men versus women. Two thirds of patients were men. Women were significantly older and had more preoperative risk factors including hypertension, diabetes mellitus, and congestive heart failure. Women also had more angina and poorer NYHA classification before surgery. The prevalence of preoperative atrial fibrillation was almost twice as high in women (22%) as in men (13%), and the percentage of women who had had a stroke before surgery was more than 40% higher.


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  		Table 1. Preoperative and Perioperative Clinical Variables of Patients Undergoing Combined Valve and Coronary Artery Bypass Graft Surgery Between January 1990 and October 2000 at Toronto General Hospital
 
The main indication for valve surgery was stenosis in patients with aortic valve disease and regurgitation in patients with mitral and tricuspid valve disease. The distribution of patients according to valve pathology was the same in both male and female patients. However, women were more likely to undergo urgent surgical procedures. Although the incidence of triple-vessel disease was identical in both groups, women received fewer distal bypass grafts and the left internal thoracic artery was used less frequently. Aortic crossclamp and CPB times were similar in both groups.

Figure 1 shows the distribution of valve procedures performed in men and women. In the aortic position (Fig 1A), tissue valves were the preferred valve type, and similar amounts of tissue and mechanical valves were implanted in women and men. Women received significantly fewer mitral valve repairs (Fig 1B), and thus more mitral valve replacements. Triscuspid procedures were performed in much smaller volumes than aortic or mitral valve operations. Tricuspid valve repair was performed in the majority of patients requiring tricuspid surgery, usually in combination with mitral or aortic valve procedures, or both (Fig 1C).


Figure 1
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  		Fig 1. Percentage of (A) aortic valve, (B) mitral valve, and (C) double- or triple-valve operations in men (black bars) and women (hatched bars) separated by type of valve procedure (ie, repair, mechanical replacement, or tissue replacement). *p < 0.05.

 
Perioperative mortality was 7% in women and 4% in men (p = 0.026). As we have previously described, female sex was an independent predictor of early death [14].

Long-term follow-up was obtained in 99.8% of patients. The majority of patients who were lost to follow-up were referred from centers outside of Ontario. The mean length of follow-up was 5.3 ± 3.2 years (range, 0 to 12.5).

Although more women than men died during follow-up (35% versus 30%), this difference did not reach statistical significance (p = 0.062; see Fig 2). Cox regression revealed the following independent predictors of long-term survival (hazard ratios and 95% confidence intervals in parentheses): age (1.23 per 5-year interval; 1.16 to 1.31), redo valve surgery (1.30; 1.01 to 1.66), mitral valve surgery (1.32; 1.08 to 1.61), left ventricular ejection fraction less than 40% (1.35; 1.10 to 1.65), peripheral vascular disease (1.38; 1.10 to 1.74), double-valve surgery (1.50; 1.08 to 2.07), diabetes mellitus (1.79; 1.47 to 2.19), chronic obstructive pulmonary disease (2.21; 1.51 to 3.23), and preoperative renal failure (2.37; 1.68 to 3.34). Female sex was not an independent predictor of survival.


Figure 2
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  		Fig 2. Univariate analysis of long-term survival in women (dashed line) and men (solid line) after combined coronary artery bypass graft and valve surgery. Numbers in center of Figure indicate 5-year (yr) and 10-year actuarial survival. Values at x-axis show number of patients available for analysis at respective time point (men, upper row; women, lower row).

 
Female patients had an increased risk of late stroke (see Fig 3). Cox regression revealed the following predictors of late stroke: age (1.19 per 5-year interval; 1.07 to 1.33), female sex (1.52; 1.1.09 to 2.12), peripheral vascular disease (1.61; 1.04 to 2.47), and use of a mechanical valve (2.21; 1.52 to 3.23).


Figure 3
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  		Fig 3. Univariate analysis of freedom from stroke in women (dashed line) and men (solid line) after combined coronary artery bypass graft and valve surgery. Numbers in center of Figure indicate 5-year (yr) and 10-year freedom from cerebrovascular accidents (CVA). Values at x-axis show number of patients available for analysis at respective time point (men, upper row; women, lower row).

 
The occurrence rates of all other long-term outcomes were low, and there were no differences between men and women by univariate or multivariable analyses. The 10-year actuarial freedom rates were (male and female, respectively) 96.4% ± 0.8% and 95.3% ± 1.2% for redo valve surgery, 68.2% ± 2.4% and 69.9% ± 3.2% for acute myocardial infarction, 78.7% ± 2.2% and 74.6% ± 3.5% for heart failure, and 96.8% ± 0.6% and 97.5% ± 0.9% for bacterial endocarditis.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
In the current study, we demonstrated that overall long-term survival is similar for men and women undergoing combined CABG and valvular surgery, despite an increased prevalence of risk factors in female patients. We also demonstrated a significantly increased risk of long-term stroke in women.

Few studies have investigated long-term sex differences in combined valve and CABG surgery [9–11]. In addition, such studies have been limited by small sample sizes. We previously compared sex-related outcomes in a large population of valve/CABG patients [14], but limited our assessment to early (namely, perioperative) morbidity and mortality. We therefore undertook the current study, the largest of its kind, to compare long-term sex-specific outcomes in patients undergoing combined cardiac procedures.

Several studies have assessed the impact of female sex on outcomes after isolated CABG surgery [4, 5, 16–19]. The results of these studies are controversial and partially contradictory. Some studies state that operative risk is higher for women than for men [4, 5, 15], and some state that there is no difference [16–18]. Interestingly, the contradictory results seem to apply only to those studies assessing short-term outcome. To the best of our knowledge, there is no study showing poorer long-term outcomes for women than for men after isolated CABG. Our analysis supports this observation in patients undergoing combined valve and CABG procedures. We found that women are at greater risk during the perioperative phase, but show similar survival during long-term follow-up. Most studies assessing sex differences for isolated valve surgery do not find female sex to be an independent risk factor for early death [11, 19, 20]. Thus, it may be hypothesized that the differences in perioperative mortality may be related to the coronary bypass portion of the operation, rather than the valve procedure.

Another interesting finding of our study is that women suffer more strokes during long-term follow-up than men. Women had a significantly higher prevalence of preoperative atrial fibrillation and stroke, which may have contributed to their increased long-term stroke rates. However, female sex continued to be a predictor of long-term stroke even after accounting for these risk factors in the Cox regression model. It could be hypothesized that the increased risk of stroke is due to an increased number of mechanical valves that were implanted in women (Fig 1).

Implantation of a mechanical valve was also an independent predictor of stroke. Unfortunately, our method of follow-up is unable to differentiate between ischemic and hemorrhagic stroke, and therefore we cannot make conclusive statements on the causes of stroke. However, further studies should be performed to elucidate the cause of the elevated risk of long-term stroke in female patients undergoing combined valve and CABG surgery.

Preoperative characteristics may have played a role in our observed long-term differences in outcomes. Several studies have demonstrated that women undergoing cardiac surgery present with more preoperative risk factors than men [21, 22]. While some of these differences may be due to true biologic variation, some may also be due to sex-related differences in patient referral [18, 23]. Propensity matching of patients would be one way to account for preoperative differences in patient groups. However, the number of patients in our study and the 2:1 distribution of men and women did not allow us to perform propensity matching.

Direct comparisons of outcomes between men and women have been questioned because of differences in disease patterns, technical surgical considerations, and life expectancy [21, 22, 24]. Thus, a similar long-term survival for women may indicate worse outcome because women live longer than men in the general population. However, our results may also be interpreted to show that women benefit just as much from combined procedures as men. We have previously demonstrated that women undergoing combined valve and CABG surgery receive fewer internal thoracic artery grafts and have a higher percentage of incomplete revascularization [14], well-recognized risk factors for long-term cardiac morbidity and mortality after surgical revascularization [13]. Thus, one would expect higher long-term mortality and more readmissions for myocardial infarction or congestive heart failure during follow-up. Yet, we failed to demonstrate any such long-term differences between men and women despite clear differences in the degree of revascularization.

Our findings are supported by King [25], who assessed recovery of contractile function after coronary revascularization. The study found that while women had more ventricular dysfunction preoperatively, contractile function 3 months postoperatively was identical between groups. Finally, Jacobs and colleagues [8] suggest a better outcome for women after coronary surgery based on similar observations, namely, women have similar long-term outcome but more preoperative risk factors. Thus, it appears that women may benefit as much from combined valve and CABG surgery as men, even though their early perioperative outcomes may be worse.

Conclusions
We demonstrate here that (1) women face a greater perioperative risk of mortality, but equal long-term survival; and (2) women have a higher risk of long-term stroke during combined coronary and valvular surgery. Our findings, if confirmed by other investigators, should lead to further studies into determining the exact cause of the increased risk of stroke and possible methods of prevention.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We wish to thank the surgeons of the Division of Cardiovascular Surgery for allowing us to review the data from the Toronto General Database. We also wish to thank Susan Collins (Database Manager), and Claus Wall (Institute for Clinical Evaluative Sciences) for performing the data linkage.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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