Female Sex as an Independent Predictor of Morbidity and Survival After Isolated Coronary Artery Bypass Grafting

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1 Female Sex as an Indeendent Predictor of Morbidity and Survival After Isolated Coronary Artery Byass Grafting Waleed A. Ahmed, MD, Philli J. Tully, M. Psych (Clin), PhD, John L. Knight, FRACS, and Robert A. Baker, PhD Cardiac and Thoracic Surgical Unit, Deartment of Medicine, Flinders Medical Centre and Flinders University of South Australia, Adelaide, South Australia, Australia; and Faculty of Medicine, Teaching Hositals, Suez Canal University, Ismailia, Egyt Background. This study sought to determine whether female sex was an indeendent risk factor for combined in-hosital morbidity, mortality, and long-term survival after coronary artery byass grafting (CABG). Methods. Data were collected rosectively for 1,114 (23.5%) women and 3,628 (76.5%) men oerated on between January 1, 1996 and December 31, 2004 with median follow-u of 7.9 years (interquartile range 3.55 to 10.5). The combined morbidity end oint was defined as in-hosital renal failure, stroke, ventilation for more than 24 hours, dee sternal wound infection, reoeration, myocardial infarction (MI), and mortality less than 30 days after discharge. The long-term all-cause and cardiac mortality outcomes were analyzed using multivariate roortional hazard regression. Results. Females were older, with body surface area, and generally had more significant comorbid conditions than did males ( < 0.05). Female sex was associated with increased odds of the combined morbidity end oint (adjusted odds ratio [OR] 1.29; 95% confidence interval, 1.04 to 1.59, 0.02). There were 868 deaths (18.3% of total samle) during the follow-u eriod, and 305 deaths (n 305 [35.1%] of deaths) were deemed to be of cardiac causes. In adjusted survival models, female sex was associated with cardiac mortality (hazard ratio [] 1.28; 95% confidence interval, 0.96 to 1.73; 0.10) but not with all-cause mortality ( 0.92; 95% confidence interval, 0.77 to 1.11; 0.38). Conclusions. Female sex was associated with early combined morbidity and long-term cardiac mortality but not long-term all-cause mortality. A greater roortion of concomitant risk factors characterize female atients undergoing CABG. (Ann Thorac Surg 2011;92:59 67) 2011 by The Society of Thoracic Surgeons The extent to which male and female atients exerience discreant mortality and morbidity outcomes after coronary artery byass grafting (CABG) has been the subject of ongoing debate [1-6]. Desite imrovements in myocardial rotection strategies and advances in surgical technique in the last 3 decades, higher mortality after CABG has been observed in women in comarison with their male counterarts [2, 7]. Multile hyotheses have been suggested to account for this aarent sex disarity, including differences in the extent of eicardial coronary artery disease (CAD), a greater roortion of microvascular dysfunction (X syndrome) [8], sex differences in molecular remodeling in ressure overload hyertrohy [9], and metabolic syndrome [10] in women. However these differences may relate to a referral bias from women resenting for diagnostic assessment and revascularization at a more advance stage of coronary artery disease [11]. In addition men and women may differ in degree of hyertension, diabetes, hyercholesterolemia, eriheral vascular disease, stable Acceted for ublication Feb 11, Address corresondence to Dr Baker, Cardiac & Thoracic Surgical Unit, Level 6 Flinders Private Hosital, Bedford Park, Adelaide South Australia, 5042; rob.baker@flinders.edu.au. and unstable angina, and congestive heart failure [8, 9]. Given such widely reorted differences, female sex might be a marker of a high-risk rofile and thus adjustment for known confounding factors would reduce the redictive value of female sex on short- and long-term mortality risk. The rimary aim of the resent study was to examine whether female sex was indeendently associated with combined morbidity and survival after isolated CABG. Patients and Methods Patients All consecutive atients scheduled for isolated CABG with cardioulmonary byass (CPB) at the Flinders Medical Centre and Flinders Private Hosital, South Australia, Australia, from January 1, 1996 to December 31, 2004 were considered eligible for the study. To make a homogeneous samle, atients were excluded from analysis if they had concomitant cardiac surgical rocedures (eg, valve reair or relacement, aortic root dissection, left ventricular aneurysm reair) or had undergone a revious oen heart rocedure. Standardized definitions of the Australian Society of Cardiothoracic Surgeons [12] 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 60 AHMED ET AL Ann Thorac Surg FEMALE SEX AND MORTALITY RISK AFTER CABG 2011;92:59 67 Table 1. Descritive Comarisons Between Male and Female Patients Undergoing CABG a Clinical and Demograhic Variables b Males (n 3,628) Females (n 1,114) n (%) n (%) Age (mean, SD) Recent MI Tobacco smoking 2, Resiratory disease Hyercholesterolemia 1, Hyertension 2, Diabetes mellitus Renal disease Periheral vascular disease Cerebrovascular disease CCS class I/II III/IV 2, LVEF Normal 60% 2, Imaired 31% to 59% Severe 30% Body surface area (mean, SD) Cardiogenic shock Surgical Variables Elective surgery Urgent surgery Emergency surgery Left internal mammary artery graft 2, Procedure time (mean, SD) CPB time median (interquartile range) Cross-clam time (mean, SD) Grafts 3 2, Intubation time median (interquartile range) a Definitions: Recent MI: Patient hositalized at any time for an MI documented in the medical record. Tobacco smoking: History confirming any form of tobacco use in the ast. Resiratory disease: chronic lung disease; atient receiving long-term inhaled or oral bronchodilator theray or long-term oral steroid theray directed at lung disease or room air Po 2 less than 60 or room air Pco 2 greater than 50 or mechanical ventilation. Hyercholesterolemia: History of hyercholesterolemia diagnosed or treated, or both, by a hysician or cholesterol levels greater than 5.0 mmol/l, high-density liorotein levels less than 1.0 mmol/l or triglyceride levels greater than 2.0 mmol/l, or a combination of these values. Hyertension: Documented history of hyertension diagnosed and treated with medication, diet, or exercise, or a combination, or blood ressure greater than 140 systolic or greater than 90 diastolic on at least two occasions or currently taking antihyertensive medication. Diabetes mellitus: History of diabetes, regardless of duration of disease or need for antidiabetic agents. Renal disease: Last serum creatinine level recorded before surgery greater than or equal to 200 mol/l, history of renal dialysis, or reciient of translant. Periheral vascular disease: The atient s history of eriheral vascular disease either aneurysmal or chronic or acute occlusion or narrowing of the arterial lumen of the aorta or extremities, including the following: claudication either with exertion or rest, amutation for arterial insufficiency, vascular reconstruction, byass rocedure, or ercutaneous intervention to the extremities, documented aortic aneurysm, documented renal artery stenosis, ositive noninvasive testing documented (eg, ankle brachial index 0.8). Cerebrovascular disease: Unresonsive coma longer than 24 hours or cerebrovascular accident (symtoms longer than 72 hours after onset), or reversible ischemic neurological deficit (recovery within 72 hours), or transient ischemic attack (recovery within 24 hours), or noninvasive carotid artery test with 50% diameter stenosis (equivalent to 75% cross sectional area stenosis). Canadian Cardiovascular Society classification (CCS class): I: Ordinary hysical activity, such as walking or climbing the stairs does not cause angina. Angina may occur with strenuous, raid, or rolonged exertion at work or recreation. II: There is slight limitation of ordinary activity. Angina may occur with moderate activity such as walking or climbing stairs raidly; walking uhill; walking or stair climbing after meals or in the cold, in the wind, or under emotional stress; or walking more than two blocks on the level, and climbing more than one flight of stairs at normal ace under normal conditions. III: There is marked limitation of ordinary hysical activity. Angina may occur after walking one or two blocks on the level or climbing one flight of stairs under normal conditions at a normal ace. IV: There is inability to carry on any hysical activity without discomfort; angina may be resent at rest. Cardiogenic shock: At the time of the rocedure, the atient is in a clinical state of hyoerfusion according to either of the following criteria: hyotension (a systolic blood ressure 90 mm Hg) or odds ratio CI less than 2.0 for at least 30 minutes or the need for suortive measures to maintain a systolic ressure greater than or equal to 90 mm Hg or a CI greater than 2.0. b n% unless otherwise indicated. CABG coronary artery byass grafting; CPB cardioulmonary byass; LVEF left ventricular ejection fraction; MI myocardial infarction; SD standard deviation. were used in this study unless otherwise secified and are defined in footnotes in Tables 1 and 2. All reoerative data were collected rosectively by resident medical officers; surgical and ostoerative values were collected by surgical staff and entered into an electronic database located on our hosital database server (SQL)

3 Ann Thorac Surg AHMED ET AL 2011;92:59 67 FEMALE SEX AND MORTALITY RISK AFTER CABG Table 2. Proortion of Combined Incident Morbidity Outcomes by Patient Sex Incident Morbidity a Total Samle (N 4,742) Males (n 3,628) Females (n 1,114) Mortality 30 days 89 (1.9) 60 (1.7) 29 (2.6) 0.04 Stroke, CVA 48 (1.0) 31 (.9) 17 (1.5) 0.05 Renal dialysis 75 (1.6) 57 (1.6) 18 (1.6) 0.92 Ventilation 24 hours 395 (8.3) 269 (7.4) 126 (11.3) Sternal wound infection 8 (0.2) 4 (0.1) 4 (0.4) 0.09 Reoeration 133 (2.8) 100 (2.8) 33 (3.0) 0.72 Myocardial infarction 167 (3.5) 122 (3.4) 45 (4.0) 0.28 Combined end oint (binary) 776 (16.4) 553 (15.2) 223 (20.0) a Morbidity consisted of any of the following: mortality during the index hositalization or within 30 days of surgery regardless of location, ermanent stroke, cerebrovascular accident or central neurologic deficit ersisting for longer than 72 hours, new requirement for renal dialysis or increase in serum creatinine level to more than 2.0 mg/dl and double the most recent reoerative creatinine level, ventilation longer than 24 hours, dee sternal wound infection, reoeration for any reason. MI was defined as at least two of the following three criteria: (1) enzyme level elevation: either creatine kinase MB level 30 or troonin level 20.0 g/l, or troonin level equivalent documented at your institution, rovided that oeration does not involve myocardial incision; (2) new wall motion abnormalities; (3) serial electrocardiograms (at least two) showing new Q waves, duration 0.03 ms in two contiguous leads. Data shown as number N and ercentage (%). CVA cerebrovascular accident. accessed through a Microsoft Access (Microsoft Cororation, Redmond, WA) user interface. Database management was maintained through regular meetings with the database manager (R.A.B.) and staff to maintain consistent data collection and accuracy, as reorted elsewhere [13, 14]. This study was erformed under the ausices of the Clinical Governance Committee of the Flinders Medical Centre; additional atient consent was not required for access to routinely collected de-identified data. Anesthetic, surgical, and CPB techniques were similar for all atients. For induction, midazolam, ancuronium, and fentanyl were used, and maintenance was with isofluorane or sevoflurane, nitrous oxide, or roofol, or a combination, as required. Patients underwent median sternotomy, and before aortic cannulation, hearin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 400 seconds or more before commencement of CPB. After harvesting the arterial or venous conduit, or both, CPB was instituted using an ascending aortic and either a two-stage right atrial or bicaval cannulation. CPB was erformed using roller ums; the circuit included a hard-shell membrane oxygenator, olyvinyl chloride or bioassive tubing (SMARxT, Cobe Cardiovascular, Arvada, CO) and a 40 arterial line filter. Routine CPB rotocol included a nonulsatile arterial flow rate of 1.8 to 2.4 L/min/m 2, alha-stat H management, gravity venous drainage, and teid systemic temerature management (30 to 36 C). Myocardial rotection was achieved by using intermittent antegrade hyerkalemic teid blood cardiolegia (30 to 36 C). The initial dose of cardiolegia solution was given for 2 minutes (250 ml/min) or until arrest occurred, followed by maintenance doses given aroximately every 20 minutes as required through the grafting rocedure. The heart was arrested, the target coronary artery was oened, and distal anastomoses between the byass graft and the native coronary artery were erformed using 7-0 or 6-0 Prolene sutures (Ethicon, Inc., Somerville, NJ) under aortic cross-claming. Ninety-five rocedures were erformed with grafting undertaken with electrical fibrillation of the heart. Proximal anastomoses were carried out on beating heart and artial aortic claming using 6-0 or 5-0 Prolene sutures. Gradual weaning from byass started after comletion of the roximal anastomoses, and rotamine was given to return the activating clotting time to reoerative levels. At the end of surgery, atients were transferred to the intensive care unit (ICU) and managed according to unit rotocol. Patient Morbidity and Survival Patient survival was ascertained by identification within the National Death Index rovided to our institution by the Australian Institute of Health and Welfare. National Death Index data rovided cause of death according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision [15] until December 31, 2008, and this date was taken as the censor date, enabling 48-month survival follow-u on the entire cohort. Cardiac-related mortality was classified as any rimary cardiovascular cause of death, ICD codes I00 to I99 [15]. Morbidity was defined in accordance with the Society of Thoracic Surgeons Working Grou Panel on the Collaborative CABG Database Project [16] who secified aroriate ostoerative combined end oints derived from 774,881 rocedures. Morbidity consisted of any of the following; mortality during the index hositalization or within 30 days of surgery regardless of location, ermanent stroke, cerebrovascular accident (CVA) or central neurologic deficit ersisting for longer than 72 hours, new requirement for renal dialysis or increase in serum creatinine level to more than 2.0 mg/dl and double the most recent reoerative creatinine level, ventilation for more than 24 hours, dee sternal wound infection, and reoeration for any reason. In addition we included myocardial infarction (MI) (Table 2 footnote).

4 62 AHMED ET AL Ann Thorac Surg FEMALE SEX AND MORTALITY RISK AFTER CABG 2011;92:59 67 Table 3. Adjusted Logistic Regression Analysis of Combined Mortality and Morbidity End Point According to Patient Sex a Model 1 (N 4,742) Model 2 Males (n 3,628) Model 3 Females (n 1,114) Variable OR uer OR uer OR uer Sex b Age BSA Recent acute MI CCS class I/II (reference) III/IV LVEF Normal (reference) Imaired Severe Urgency of oeration Elective (reference) Urgent Emergency Hyercholesterolemia Hyertension Diabetes Tobacco smoking Resiratory disease Renal disease Periheral vascular disease Cardiovascular disease Distal grafts Left internal mammary artery graft Procedure time (min) C-index (SE), AUC 0.64 (0.01) (.01) (0.02) Goodness of fit 2 (8) 3.67, (8) 6.55, (8) 8.07, 0.43 a Morbidity end oint: renal failure, dee sternal wound infection, stroke, reoeration, intubation longer than 24 hours, mortality less than 30 days after discharge [16] and myocardial infarction. b Female sex, odds ratio adjusted for covariates. AUC area under the curve; BSA body surface area; CCS Canadian Classification System; CI confidence interval; LVEF left ventricular ejection fraction; MI myocardial infarction; OR odds ratio; SE standard error. Statistical Analysis Data analysis was erformed with SPSS 18.0 (SPSS Inc., Chicago, IL). Descritive comarisons between the sexes on demograhic and surgical variables used indeendent samles t test, Mann-Whitney U test, and the 2 statistic with Fisher s exact test as aroriate. Covariates for morbidity and mortality analyses were determined a riori from revious research [1, 2, 6, 7, 10, 13, 16] and included the categorical variables: angina Canadian Classification System (CCS) class III/IV versus I/II, recent acute MI ( 30 days), diabetes mellitus, left ventricular ejection fraction (LVEF) (severely imaired 30%, imaired 31% to 59%, normal 60%), hyercholesterolemia, hyertension, renal disease, eriheral vascular disease, resence of cerebrovascular disease, tobacco smoking history, resiratory disease, urgency of surgery (elective versus urgent versus emergency), use of left internal mammary artery (LIMA), and three distal grafts or more versus three grafts or less. Continuous variables included age, total rocedure time (minutes), and atient body surface area (m 2 ). There were too few cases of atients resenting in cardiogenic shock to be considered for multivariate analyses (n 21, 0.4%). The 30-day combined morbidity and mortality end oint was analyzed using multivariate logistic regression emloying male sex as the reference category, adjusted for covariates. Logistic regression model discriminatory and fit indices included the Hosmer Lemeshow goodness-of-fit test and the c-index. Long-term mortality (ie, all-cause and cardiac-related events) was analyzed unadjusted with the log-rank test. Adjusted analyses emloyed multivariate Cox roortional hazard modeling, allowing for all the reviously mentioned covariates regardless of association with survival. Three regression models were analyzed and are reorted for morbidity end oint and survival. In Model 1 (all atients, N

5 Ann Thorac Surg AHMED ET AL 2011;92:59 67 FEMALE SEX AND MORTALITY RISK AFTER CABG 63 Fig 1. Kalan-Meier actuarial survival curves for all-cause mortality comaring atients by sex according to males (solid line) and females (broken line). The associated log-rank test for actuarial survival was 2 (1) 6.13, ,742) covariates were entered into the logistic or hazard model in block fashion at the first ste, followed by atient sex (male sex as reference category) to determine the effect on morbidity and mortality indeendent of other known covariates. Two searate regression models were then run according to sex (Model 2, males only, n 3,628) and (Model 3, females only, n 1,114) with adjustment for the reviously mentioned covariates to determine the unique risk factors for each sex. During data screening there were no outliers that influenced hazard models, and multicollinearity statistics were accetable as determined by squared multile correlations less than 0.90 and insection of correlations between regression coefficients [17]. The roortionality of hazards assumtion was checked initially by entering covariates as interactions with time and also ascertained grahically in final models by examination of the baseline hazards function lot, the log-minus-log lot of survival function, and the Schoenfeld residuals. Results Demograhic Data and Preoerative Characteristics Among the 4,742 consecutive and isolated CABG rocedures erformed, 1,114 atients were female (23.5%) and 3,628 were male (76.5%). As seen in Table 1, females tended to be older, have smaller body surface area, and were characterized by a significantly greater roortion of clinical risk factors. Females were also more likely to have undergone urgent or emergency surgery, received fewer internal mammary artery conduits comared with males, and were less likely to receive more than three grafts than were male atients. Analysis for linear trend and insection of the raw data suggested that there was a significant increase in the roortion of females over time ( 2 (8) 16.48; 0.04). 30-Day Combined Morbidity Outcome There were 776 (16.4%) ersons who exerienced any morbidity end oint, the most common singular outcome being ventilation times greater than 24 hours (descritives shown in Table 2). Sex comarisons showed that the roortion of 30-day morbidity was greater among females for mortality, stroke/cva, ventilation longer than 24 hours, and the combined morbidity end oint. Analysis for linear trend over time was not significant ( 2 (8) 11.06; 0.20), suggesting no significant change in the roortion of morbidity outcomes over time. An adjusted analysis of combined morbidity according to atient sex is shown in Table 3 (Model 1) and suggested that female sex was associated with greater odds for combined morbidity (adjusted odds ratio 1.29; 95% confidence interval, 1.04 to 1.59; 0.02), although the effect aeared to be modest. The searate regression models for males and females (Table 3, Models 2 and 3) demonstrated articular covariate findings evident in males, including that older age and renal disease were associated with a greater odds for morbidity in contrast to females. All-Cause Mortality There were 37,052 erson years of survival for analyses with a median follow-u of 7.9 years (interquartile range 3.55 to 10.5). There were 868 deaths (18.3% of total

6 64 AHMED ET AL Ann Thorac Surg FEMALE SEX AND MORTALITY RISK AFTER CABG 2011;92:59 67 Table 4. Adjusted Hazard Models for Long-Term All-Cause Mortality According to Patient Sex Model 1 (N 4,742) Model 2 Males (n 3,628) Model 3 Females (n 1,114) Variable uer uer uer P Sex a Age BSA Recent acute MI CCS Class I/II (reference) III/IV LVEF Normal (reference) Imaired Severe Urgency of oeration Elective (reference) Urgent Emergency Hyercholesterolemia Hyertension Diabetes Tobacco smoking Resiratory disease Renal disease Periheral vascular disease Cardiovascular disease Distal grafts Left internal mammary artery graft Procedure time (min) a Female sex, hazard ratio adjusted for covariates. BSA body surface area; CCS Canadian Classification System; CI confidence interval; hazard ratio; LVEF left ventricular ejection fraction; MI myocardial infarction. samle) during the follow-u eriod; 636 were male and 232 female. All-cause survival at 5 years was 85% and 82% for males and females, resectively, whereas at 10 years survival was 71% and 64% for males and females, resectively. A log-rank test suggested that females exerienced greater mortality ( 2 (1) 6.13, 0.01), as shown in the actuarial survival lot (Fig 1). Unadjusted analysis of all-cause mortality suggested that females were at aroximately 20% increased risk of mortality (, 1.21;, 1.04 to 1.41; 0.01). As can be seen in Table 4 Model 1, after adjustment for covariates female sex did not increase the risk of long-term mortality (, 0.92;, 0.77 to 1.11; 0.38). When the hazard model analyses were reeated searately for male and female atients (Table 4, Model 2s and 3, resectively) risk factors identified in males but not females included diabetes and eriheral vascular disease, and LVEF less than or equal to 30%. Conversely, increase in body surface area (BSA) was identified only in females to the mortality risk ( 0.35;, 0.15 to 0.84; 0.02), suggesting that BSA is associated with greater mortality. The adjusted roortional all-cause survival is shown grahically in Figure 2, suggesting that after adjustment for covariates there was no difference in survival outcome by sex. Cardiac-Related Mortality There were 305 deaths (35.1% of all deaths) deemed to be of cardiac-related causes; 206 male and 99 female. Unadjusted analysis suggested that female sex was associated with less than two-fold increased risk of cardiac-related mortality (, 1.60;, 1.26 to 2.04; 0.001}. The was attenuated after adjustment for covariates as shown in Table 5 Model 1 (, 1.28, 95% CI, 0.96 to 1.73; 0.10). Resiratory disease was associated with greater risk of cardiac-related mortality in females (Table 5, Model 3), whereas the number of distal grafts was not associated with cardiacrelated mortality risk in females (Table 5, Model 3). There were too few deaths and cases deemed to be at risk to rovide a meaningful grahic reresentation of cardiac mortality.

7 Ann Thorac Surg AHMED ET AL 2011;92:59 67 FEMALE SEX AND MORTALITY RISK AFTER CABG Fig 2. Proortional survival curves for all-cause mortality adjusted for covariates comaring atients by sex according to males (solid line) and females (broken line). The associated adjusted hazard ratio for female sex was 0.92;, 0.77 to 1.11, Comment The main findings were that among 4,742 consecutive and isolated CABG atients, female sex was an indeendent redictor of 30-day morbidity and bore no association with all-cause mortality in the long term. Insection of the actuarial survival lot in Figure 1 corroborates that females had a greater early mortality risk not sustained in the longer term. There was a modest effect size suggesting greater risk for cardiac-related mortality in females; however, only 35% of deaths were deemed to be of cardiac-related causes. The results here and elsewhere [4, 6, 18, 19] suggest that long-term survival after isolated CABG can be attributed to comorbidity risk factors rather than female sex. Our study, suorting revious reorts, showed that females generally had a higher roortion of comorbid conditions [1, 19-21]. Female sex was associated with 29% increased odds for 30-day combined morbidity indeendent of the variance attributable to a range of clinical variables such as older age, LVEF, body surface area, and higher CCS class, similar to findings elsewhere [7, 10]. Females exerienced a greater roortion of ostoerative mortality, stroke, and extended ventilatory suort but were no different than males with resect to renal dialysis, reoeration, and MI. Vaccarino and colleagues [10] examined in-hosital mortality among 36,009 male and 15,178 female atients and reorted that females younger than 50 years were at 3 times greater risk of ostoerative mortality comared with men of similar age. Ranucci and colleagues [22] showed that female sex was associated with severe intraoerative hemodilution necessitating lasma and latelet transfusion and suggested that these factors were related to adverse short-term outcomes. The results described here should however take into consideration the revious studies that have adjusted for discreant comorbidity rofiles by using roensity matching and found sex to bear no influence on ostoerative mortality outcome [1, 18, 19, 23]. Another general consideration is that the risk factors identified for early morbidity tyically reflected acute conditions such as the urgency of CABG, renal dysfunction, imaired LVEF, and total rocedure time. In this study females had more urgent and emergent surgery in comarison to males. Studies have suggested that females may be referred for CABG less often than males, and ossibly later in the course of disease. The referral bias may contribute to higher 30-day mortality (3,18,19). Secifically, females were characterized by a greater roortion of some risk factors associated with an increased risk of long-term mortality in Model 1 (Table 4), including older age, resiratory disease, eriheral vascular disease, cerebrovascular disease, diabetes mellitus, left ventricular dysfunction, and hyercholesterolemia. This arallels the results of Guru and colleagues [19] who reorted that females were characterized by a greater incidence of diabetes, chronic obstructive ulmonary disease, eriheral vascular disease, cerebrovascular disease, and heart failure yet had equal or better long-term survival when comared with males. The results of the comarative survival models identified several mortality risk factors that affected males but not females, including resiratory disease, diabetes, and eriheral vascular disease, whereas BSA was identified only among females to increase the long-term mortality risk. A similar discreancy was reorted by Mickleborough and colleagues [4], as survival in females was redicted by history of recent MI and CVA, whereas in contrast CCS class IV symtoms, smaller BSA, and lack of left internal thoracic artery were indeendent redictors only in males. Lower BSA may be related to the comlex relationshi between smaller the BSA and smaller native coronary artery target that affect graft atency and an increased risk of late myocardial infarction [18, 25]. The revascularization technique may have an imact on survival, as in this situation females received fewer internal mammary artery conduits and the total number of conduits was consistent with other findings [1, 4]. Also, the survival benefit attributable to the left internal mammary artery graft was afforded to only men with resect to all-cause mortality, although use of the left internal mammary artery graft had a significant effect on cardiacrelated mortality among all atients regardless of sex (Table 5). Guru and colleagues [19] concluded that more durable revascularization techniques should be adoted in females, although others have suggested that females acceted for CABG have less diffuse disease and a comarable number of small vessels smaller than 1.5 mm [4]. These findings are resented with several limitations, including the observational cross-sectional study design with a median follow-u of 7.9 years. Also, given the frequency of cardiac-related deaths, cometing risks cannot be ruled out, whereas the influence of reeated revascularization rocedures was not ascertained. A re- 65

8 66 AHMED ET AL Ann Thorac Surg FEMALE SEX AND MORTALITY RISK AFTER CABG 2011;92:59 67 Table 5. Adjusted Hazard Models for Long-Term Cardiac Mortality According to Patient Sex a Model 1 (N 4,742) Model 2 Males (n 3,628) Model 3 Females (n 1,114) Variable uer uer uer Sex b Age BSA Recent acute MI CCS Class I/II (reference) III/IV LVEF Normal (reference) Imaired Severe Urgency of oeration Elective (reference) Urgent Emergency Hyercholesterolemia Hyertension Diabetes Tobacco smoking Resiratory disease Renal disease Periheral vascular disease Cardiovascular disease Distal grafts Left internal mammary artery graft Procedure time (min) a Cardiac mortality ICD 10 th Revision codes I00 I99 [15]; b Female sex, hazard ratio adjusted for covariate BSA body surface area; CCS Canadian Classification System; CI confidence interval; hazard ratio; LVEF left ventricular ejection fraction; MI myocardial infarction. duced mortality risk attributable to hyercholesterolemia using the Australasian Society for Cardiac and Thoracic Surgeons data definitions has been reorted elsewhere [24] and is susected to encomass the effects of liiding treatment. Analysis of in-hosital morbidity outcomes yielded a modest discriminatory regression model not uncommon with resect to CABG outcomes [25], suggesting otential omission of imortant risk factors. Additionally, the influence of intraoerative and erfusion variables on atient outcomes could not be assessed in further detail, as the eriod of the study includes time intervals before the introduction of electronic erfusion records. In conclusion, this study showed that in comarison to men, female atients undergoing isolated CABG were characterized by more comorbid conditions and were at greater risk for early ostoerative morbidity. In contrast, female sex had no imact on long-term mortality after CABG once adjustment was made for covariates. The divergence in findings emhasizes the need for better understanding of the risk factor rofile of females with susected MI and those acceted for CABG. References 1. Woods SE, Noble G, Smith JM, Hasselfeld K. The influence of gender in atients undergoing coronary artery byass graft surgery: an eight-year rosective hositalized cohort study. J Am Coll Surg 2003;196: Fu SP, Zheng Z, Yuan X, et al. Imact of off-um techniques on sex differences in early and late outcomes after isolated coronary artery byass grafts. Ann Thorac Surg 2009;87: Kim C, Redberg RF, Pavlic T, Eagle KA. A systematic review of gender differences in mortality after coronary artery byass graft surgery and ercutaneous coronary interventions. Clin Cardiol 2007;30: Mickleborough LL, Carson S, Ivanov J. Gender differences in quality of distal vessels: effect on results of coronary artery byass grafting. J Thorac Cardiovasc Surg 2003;126: Guth AA, Hiotis K, Rockman C. Influence of gender on surgical outcomes: does gender really matter? J Am Coll Surg 2005;200: Toumoulis IK, Anagnostooulos CE, Balaram SK, et al. Assessment of indeendent redictors for long-term mortality between women and men after coronary artery byass grafting: are women different from men? J Thorac Cardiovasc Surg 2006;131:

9 Ann Thorac Surg AHMED ET AL 2011;92:59 67 FEMALE SEX AND MORTALITY RISK AFTER CABG 7. Blankstein R, Ward RP, Arnsdorf M, Jones B, Lou YB, Pine M. Female gender is an indeendent redictor of oerative mortality after coronary artery byass graft surgery: contemorary analysis of 31 Midwestern hositals. Circulation 2005;112:I Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly revalent in women with chest ain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J 2001;141: Jacobs AK. Coronary revascularization in women in 2003: sex revisited. Circulation 2003;107: Vaccarino V, Abramson JL, Veledar E, Weintraub WS. Sex differences in hosital mortality after coronary artery byass surgery: evidence for a higher mortality in younger women. Circulation 2002;105: Hartz RS, Swain JA, Mickleborough L. Sixty-year ersective on coronary artery byass grafting in women. J Thorac Cardiovasc Surg 2003;126: Reid CM, Rockell M, Skillington PD, et al. Initial twelve months exerience and analysis for from the Australasian Society of Cardiac and Thoracic Surgeons Victorian database roject. Heart Lung Circ 2004;13: Ahmed WA, Tully PJ, Baker RA, Knight JL. Survival after isolated coronary artery byass grafting in atients with severe left ventricular dysfunction. Ann Thorac Surg 2009; 87: Rohde SL, Baker RA, Tully PJ, Graham S, Cullen H, Knight JL. The reoerative and intraoerative factors associated with long-term survival in octogenarian cardiac surgery atients. Ann Thorac Surg 2010;89: World Health Organization, International Statistical Classification of Diseases and Related Health Problems 10th Revision Version for Available at htt:// classifications/as/icd/icd10online/. 16. Shahian DM, O Brien SM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: art 1 coronary artery byass grafting surgery. Ann Thorac Surg 2009;88:S Tabachnick BG, Fidell LS: Using multivariate statistics. 4th ed. Boston, MA, Allyn and Bacon, Parolari A, Dainese L, Naliato M, et al. Do women currently receive the same standard of care in coronary artery byass graft rocedures as men? A roensity analysis. Ann Thorac Surg 2008;85: Guru V, Fremes SE, Austin PC, Blackstone EH, Tu JV. Gender differences in outcomes after hosital discharge from coronary artery byass grafting. Circulation 2006;113: Edwards FH, Ferraris VA, Shahian DM, et al. Gendersecific ractice guidelines for coronary artery byass surgery: erioerative management. Ann Thorac Surg 2005;79: Williams MR, Choudhri AF, Morales DL, Helman DN, Oz MC. Gender differences in atients undergoing coronary artery byass surgery, from a mandatory statewide database. J Gend Secif Med 2000;3: Ranucci M, Pazzaglia A, Bianchini C, Bozzetti G, Isgro G. Body size, gender, and transfusions as determinants of outcome after coronary oerations. Ann Thorac Surg 2008; 85: Koch CG, Weng YS, Zhou SX, et al. Prevalence of risk factors, and not gender er se, determines short- and longterm survival after coronary artery byass surgery. J Cardiothorac Vasc Anesth 2003;17: Reid C, Billah B, Dinh D, et al. An Australian risk rediction model for 30-day mortality after isolated coronary artery byass: The AusSCORE. J Thorac Cardiovasc Surg 2009;138: Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G. Risk of assessing mortality risk in elective cardiac oerations: age, creatinine, ejection fraction, and the law of arsimony. Circulation 2009;119: