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Do in-hospital outcomes of isolated coronary artery bypass grafting vary between male and female octogenarians?

Abstract OBJECTIVES Female gender and advanced age are regarded as independent risk factors for adverse outcomes after isolated coronary artery bypass grafting (CABG). There is paucity of evidence comparing outcomes of CABG between male and female octogenarians. We aimed to analyse in-hospital outcomes of isolated CABG in this cohort. METHODS All octogenarians that underwent isolated CABG, from January 2000 to October 2017, were included. A retrospective analysis of a prospectively collected cardiac surgery database (PATS; Dendrite Clinical Systems, Oxford, UK) was performed. A propensity score was generated for each patient from a multivariable logistic regression model based on 25 pre-treatment covariates. A total of 156 matching pairs were derived. RESULTS Five hundred and sixty-seven octogenarians underwent isolated CABG. This included 156 females (mean age 82.1 [SD: 0.9]) and 411 males (mean age 82.4 [SD: 2.1 years]). More males were current smokers (P = 0.002) with renal impairment (P = 0.041), chronic obstructive pulmonary disease (P = 0.048), history of cerebrovascular accident (P = 0.039) and peripheral vascular disease (P = 0.027) while more females had New York Heart Association class 4 (P = 0.02), left ventricular ejection fraction 30–49% (P = 0.038) and left ventricular ejection fraction <30% (P = 0.049). On-pump, CABG was performed in 140 males and 52 females (P = 0.921). There was no difference in in-hospital mortality (5.4% vs 6.4%; P = 0.840), stroke (0.9% vs 1.3%; P = 0.689), need for renal replacement therapy (17.0% vs 13.5%; P = 0.732), pulmonary complications (9.5% vs 8.3%; P = 0.746) and sternal wound infection (2.7% vs 2.6%; P = 0.882). The outcomes were comparable for the propensity-matched cohorts. CONCLUSIONS No gender difference in outcomes was seen in octogenarians undergoing isolated CABG.


INTRODUCTION
It is widely recognized that the female gender is associated with increased perioperative mortality and morbidity after coronary artery bypass grafting (CABG) [1,2]. Delayed presentation for treatment, delayed recognition of coronary artery disease with increased incidence of acute coronary syndrome, smaller body size with smaller coronary artery size making bypass grafting more challenging as well as increased incidence of comorbidities including diabetes, hypertension and hypercholesterolaemia are some of the plausible explanations for these gender differences in outcomes [3][4][5][6][7].
Advanced age is also a significant predictor of 30-day mortality and postoperative complications after CABG [8,9]. Octogenarians have several comorbidities such as renal insufficiency, chronic obstructive pulmonary disease, peripheral vascular disease and degenerative cerebral disease that make them high risk for CABG [10]. Despite these comorbidities, a significant number of octogenarians now undergo CABG.
Female gender and advanced age are regarded as independent risk factors for morbidity and mortality after CABG by the 2 most commonly used risk stratification scores, namely EuroSCORE II and STS risk score [11]. Interestingly, gender differences in mortality and morbidity have been predominantly analysed for patients <70 years of age [12]. There is paucity of evidence comparing outcomes of CABG between male and female octogenarians. The aim of our study was to analyse whether or not inhospital outcomes of isolated CABG vary between male and female octogenarians.

Study sample
This study comprised a retrospective analysis of a prospectively collected cardiac surgery database (PATS; Dendrite Clinical Systems, Ltd, Oxford, UK). Because of its retrospective nature, informed consent was waived for this study. The PATS database captures detailed information on a wide range of preoperative, intraoperative and hospital postoperative variables (including complications and mortality) for all patients undergoing cardiac surgery in our institution. The database was collected and reported in accordance with the Society for Cardiothoracic Surgery in Great Britain and Ireland database criteria. In addition, the medical notes and charts of all the study patients were reviewed.
From January 2000 to October 2017, all male and female octogenarians that underwent isolated first-time CABG at our institution were included in this study. Octogenarians that had reoperative CABG or combined procedures were excluded. The patient characteristics of both groups are shown in Tables 1 and  2. Indications for surgical intervention were determined at a weekly review involving cardiologists, cardiac surgeons and cardiac radiologists. The patients were placed on a specific waiting list according to the urgency of their procedure.

Operative technique
We have previously described our operative technique in detail [10]. Minimally invasive direct coronary artery bypass (MIDCAB) procedure was performed for isolated proximal left anterior descending artery stenosis in all but one case. All MIDCAB procedures were performed through a left anterior small thoracotomy on the beating heart. Patients with multivessel coronary artery disease underwent multivessel CABG. Median sternotomy approach was used for all multivessel CABG. The choice of on-or off-pump strategy was based on the surgeon's preference.
Left internal mammary artery (LIMA) was used for all MIDCAB procedures whereas all patients underwent multivessel CABG using varying combinations of left and/or right internal mammary artery, radial artery and saphenous vein grafts. The choice of conduits was based on the surgeon's preference as well as dictated by patient characteristics. The intraoperative data are summarized in Tables 3 and 4.

Postoperative management
Postoperative intensive care unit management was standardized for all patients. All patients received intravenous nitroglycerine (0.1-8 mg/kg/min) infusions for the first 24 h unless hypotensive (systolic blood pressure <90 mmHg). Choice of inotropic agents was dictated by the haemodynamic data. Other routine medications included daily aspirin and resumption of cholesterollowering agents and beta-blockers unless contraindicated.
Diuretics, angiotensin-converting enzyme inhibitors, other antihypertensive agents and oral anticoagulants were gradually introduced when indicated clinically.

Variables and data collection
Preoperative variables of interest included angina (Canadian Cardiovascular Society class), dyspnoea (New York Heart Association class), diabetes, hypercholesterolaemia, hypertension, smoking history, renal insufficiency [preoperative serum creatinine, > _200 mM/l, moderately impaired renal function (50-85 ml/ min), severely impaired renal function (<50 ml/min) off dialysis, and on dialysis], chronic obstructive pulmonary disease (longterm use of bronchodilators or steroids for lung disease), history of cerebrovascular disease, peripheral vascular disease, recent myocardial infarction (within 90 days), previous percutaneous coronary intervention, left ventricular ejection fraction, urgency (operation performed <24 h vs >24 h from time of referral), number of diseased vessels, left main stem and logistic EuroSCORE.
Intraoperative variables of interest included use of cardiopulmonary bypass (CPB), CPB time, aortic cross-clamp time, conversion to CPB, number of grafts, types of grafts used and index of completeness of revascularization (ICOR). The ICOR was defined as the total number of distal grafts constructed divided by the number of the affected coronary vessels reported on the preoperative coronary angiogram [13]. Complete revascularization was assumed when the ICOR was 1 or greater.
Postoperative variables of interest included myocardial infarction (creatine kinase-MB rise to >10Â the upper reference limit as a standalone measure or >5Â the upper reference limit with supporting electrocardiographic, angiographic or imaging evidence of myocardial ischaemia), reoperation for bleeding, blood product usage, pulmonary complications (chest infection, reintubation, pneumothorax, pleural effusion, tracheostomy), stroke (transient or permanent), sternal wound infection (superficial or deep), renal complications (acute kidney injury, haemofiltration, dialysis), gastrointestinal complications, length of intensive care unit stay, length of hospital stay and in-hospital mortality.

Ethical statement
All patient identifiable information was removed prior to database analysis. As part of the surgical consent process at our unit all patients consent to the use of their clinical data for research and teaching purposes. As this analysis was performed on retrospective anonymized data, the local ethics committee advised us that any further ethical approval was not required.

Statistical analysis
Statistical analysis was performed using the SAS for Windows version 9.3 (SAS, Cary, NC USA). The summary results for numeric variables were presented as mean (SD). The summary results for categorical variables were presented as frequency and percentage. The Chi-squared test was used to compare the categorical variables. The numeric variables were tested for normality, and the Mann-Whitney U-test or the 2-tailed, independent-samples Student's t-test was used accordingly. Statistical significance was defined as P < 0.05. Propensity score (PS) matching was used to reduce the effect of gender-selection bias. PS was estimated by multivariable logistic regression analysis with a binary dependent variable representing female versus male. Independent variables included all the preoperative variables (Table 1). Patients were 1:1 matched on the logit of the PS using a  calliper of width equal to 0.25 standard deviation of the logit of PS.
To detect imbalances in baseline covariates, standardized mean differences were used. Standardized mean differences represent the difference in means between the 2 groups in units of standard deviation. They do not depend on the unit of measurement and are not influenced by sample size. Standardized mean differences of <0.10 (10%) are likely to indicate a negligible imbalance between the 2 groups. Paired-samples t-test and McNemar's test were used for comparison of propensitymatched groups.
Females represented 27.5% of the study cohort. They had a higher prevalence of New York Heart Association class 4 (P = 0.02), left ventricular ejection fraction 30-49% (P = 0.038) and left ventricular ejection fraction <30% (P = 0.049). On the other hand, more males were current smokers (P = 0.002) with renal impairment (P = 0.041), chronic obstructive pulmonary disease (P = 0.048), history of cerebrovascular accident (P = 0.039) and peripheral vascular disease (P = 0.027). The preoperative variables for the matched cohorts are summarized in Table 2. After matching, treated patients were similar with regards to all baseline covariates used for PS estimation. Matching reduced covariate imbalance and improved covariate balance across treatment groups.
A total of 33 MIDCAB procedures and 534 multivessel CABG were performed for the entire cohort during the study period. Off-pump CABG was the predominant surgical revascularization strategy with 66.1% of the procedures performed without CPB. There was no gender disparity in the use of LIMA with 100% use in both groups. However, more male patients received bilateral internal mammary arteries only (P = 0.041) and bilateral internal mammary arteries with supplemental saphenous vein grafts (P = 0.027). Despite, differences in the use of bilateral internal mammary arteries, the ICOR for male and female cohorts was similar (1.  Table 3 for unmatched cohorts. Table 5 summarizes the comparison of key in-hospital postoperative outcomes for unmatched cohorts. Both groups reported similar outcomes except for the rate of renal complications. The rate of renal complications (including use of haemofiltration) was higher for males although the difference failed to reach statistical significance (P = 0.052). There was no mortality in the MIDCAB cohort.
Matching on estimated PS made available a matched cohort of 312 patients, including 156 patients in each group with similar demographic, clinical and angiographic risk profiles ( Table 2). The intraoperative variables (Table 4) and the postoperative outcomes (Table 6) were comparable for the propensity-matched cohorts as well (Figure 1) .

DISCUSSION
The key findings of this study are that in-hospital outcomes of isolated CABG do not vary between unmatched and matched male and female octogenarians.
Gender differences in outcomes of CABG remain a contentious issue. However, a large volume of published evidence reports female gender as a well-established risk factor for increased postoperative morbidity and mortality after isolated CABG [1,2]. Interestingly, most studies reporting female gender as an independent risk factor for poor outcomes after CABG analysed patients <70 years of age [12] with a paucity of evidence  [12]. We attribute this lack of gender differences in outcomes for our cohort to extensive use of off-pump revascularization strategy, aggressive use of LIMA and adherence to complete revascularization as reflected by similar ICOR for the 2 cohorts. There is evidence to suggest that off-pump CABG disproportionately benefits women and narrows the gender disparity in outcomes [15,16]. Off-pump CABG attenuates the inflammatory response associated with CPB and preserves organ function [17]. This benefit is more pronounced for high-risk cohorts of patients including women and octogenarians [10,15,16,18]. In addition, off-pump CABG reduces haemodilution and transfusion requirements which has a beneficial impact on patients with small body surface area particularly females [19]. Traditionally, females undergoing CABG have received fewer bypass grafts with underutilization of LIMA [20]. There is evidence to suggest that complete revascularization with aggressive use of arterial grafts particularly LIMA for grafting the left anterior descending artery improves outcomes in octogenarians [21]. We believe that 100% LIMA usage with similar ICOR reflecting completeness of revascularization could also account for comparable outcomes for male and female octogenarians in our study.
One of the criticisms of our study is the high mortality rate of our octogenarian cohort. However, overall mortality rate of 5.6% for our cohort is better than that reported by Arif et al. [12] (11.2%), Peterson et al. [14] (11.1%), Scott et al. [22] (9.0%) and comparable to the 5.1% reported by Bardacki et al. [23]. Importantly, our institutional mortality has continued to decline over the years (Table 7). This improvement is a reflection of the concomitant improvement in preoperative optimization of this high-risk cohort as well as the advances in anaesthetic management, surgical techniques and technology as well as postoperative care and rehabilitation. Similarly, there has been a remarkable improvement in length of hospital stay from nearly 12.5 days to around 7 days over the last 17 years. The discharge of octogenarians to home is a complex process. The presence of comorbid conditions, social circumstances, delayed healing and enhanced predisposition to postoperative complications are some of the key determinants of length of hospital stay [23]. Attention to modifiable factors, creation of a discharge support service and establishment of an active postoperative rehabilitation programme are some of the interventions that have enabled us to reduce the length of stay for octogenarians in our institution.
After cardiac surgery, acute kidney injury of varying severity occurs in up to one-third of all patients and approximately 2% require temporary renal replacement therapy [24]. Elderly patients are at a much increased risk of developing this complication. The pathogenesis of acute renal insult after cardiac surgery is multifactorial and may develop from a combination of impaired autoregulation caused by comorbidities and drugs, affected renal perfusion due to altered haemodynamics during the operation and in the perioperative period, and the procedureinduced systemic inflammatory response [25]. The rate of renal complications of 16% including the use of renal replacement therapy for our cohort is better than that reported by other authors [25,26]. We attribute this relatively low rate of renal complications to possible case selection as well as active identification of high-risk patients for renal complications, optimization of renal perfusion and avoidance of nephrotoxins.

Limitations
Our study has all the limitations attributed to a single-centre, retrospective analysis. We used PS matching to address differences  in risk profiles of the 2 groups. However, outcomes are multifactorial and also influenced by unmeasured confounders and hidden biases that may have affected our results. Furthermore, lack of angiographic assessment of graft patency and information about the cause of death are additional limitations of this analysis. Most importantly, the study spans a period of 17 years. This is both a strength of the paper as well as a very important confounder. During this period, several surgeons operated on these patients and their techniques and outcomes may have differed besides having a temporal relationship with outcome. Similarly, off-pump coronary artery bypass and MIDCAB have been more commonly utilized in the latter period of the study and at least in the initial part of the study a selection bias regarding cases taken up for off-pump coronary artery bypass cannot be excluded. One could argue that there is a need for a randomized multicentre trial to provide robust evidence to address this controversial issue. However, such a trial will be difficult to conduct as calculation of sample size can be a complex issue impacted by the choice of primary endpoint as well as the occurrence rate of chosen endpoint at the participating centres. The sample size will vary significantly depending on whether death alone or a composite of death or a major adverse event (myocardial infarction, stroke, acute renal failure requiring renal replacement therapy or repeat revascularization) within 30 days is chosen as the primary endpoint. In addition, whether the trial will use an 'all comer' approach or will have strict selection criteria may determine if the results will be representative for a large and well-defined patient population.

CONCLUSION
No gender difference in outcomes was seen in octogenarians undergoing isolated CABG in this single-centre study.
Conflict of interest: none declared.