Sex differences in outcomes after coronary artery bypass grafting: a pooled analysis of individual patient data

Mario Gaudino; Antonino Di Franco; John H Alexander; Faisal Bakaeen; Natalia Egorova; Paul Kurlansky; Andreas Boening; Joanna Chikwe; Michelle Demetres; Philip J Devereaux; Anno Diegeler; Arnaldo Dimagli; Marcus Flather; Irbaz Hameed; Andre Lamy; Jennifer S Lawton; Wilko Reents; N Bryce Robinson; Katia Audisio; Mohamed Rahouma; Patrick W Serruys; Hironori Hara; David P Taggart; Leonard N Girardi; Stephen E Fremes; Umberto Benedetto

doi:10.1093/eurheartj/ehab504

. 2021 Aug 2;43(1):18–28. doi: 10.1093/eurheartj/ehab504

Sex differences in outcomes after coronary artery bypass grafting: a pooled analysis of individual patient data

Mario Gaudino ^1,^✉, Antonino Di Franco ¹, John H Alexander ², Faisal Bakaeen ³, Natalia Egorova ⁴, Paul Kurlansky ⁵, Andreas Boening ⁶, Joanna Chikwe ⁷, Michelle Demetres ⁸, Philip J Devereaux ⁹, Anno Diegeler ¹⁰, Arnaldo Dimagli ¹¹, Marcus Flather ¹², Irbaz Hameed ¹, Andre Lamy ⁹, Jennifer S Lawton ¹³, Wilko Reents ¹⁰, N Bryce Robinson ¹, Katia Audisio ¹, Mohamed Rahouma ¹, Patrick W Serruys ¹⁴, Hironori Hara ¹⁴, David P Taggart ¹⁵, Leonard N Girardi ¹, Stephen E Fremes ¹⁶, Umberto Benedetto ¹¹

¹ Department of Cardiothoracic Surgery, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065, USA

² Department of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, 40 Duke Medicine Cir, Durham, NC 27710, USA

³ Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Carnegie Ave, Cleveland, OH 44103, USA

⁴ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA

⁵ Department of Surgery, Center for Innovation and Outcomes Research, Columbia University Medical Center, 622 W 168th St, New York, NY 10032, USA

⁶ Department of Cardiovascular Surgery, Justus-Liebig University Gießen, , Ludwigstraße 23, Gießen 35390, Germany

⁷ Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd #2900A, Los Angeles, CA 90048, USA

⁸ Samuel J. Wood Library and C.V. Starr Biomedical Information Center, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065, USA

⁹ Population Health Research Institute, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada

¹⁰ Department Cardiac Surgery, Cardiovascular Center Bad Neustadt/Saale, Von-Guttenberg-Straße 11, Bad Neustadt/Saale 97616, Germany

¹¹ Bristol Heart Institute, University of Bristol, Terrell St, Bristol BS2 8ED, UK

¹² Research and Development Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Ln, Norwich NR4 7UY, UK

¹³ Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA

¹⁴ Department of Cardiology, National University of Ireland, University Rd, Galway, Ireland

¹⁵ Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK

¹⁶ Schulich Heart Centre Sunnybrook Health Sciences Centre, University of Toronto, Hospital Road, Toronto, ON M4N 3M5, Canada

^✉

Corresponding author. Tel: +1 212 746 9440, Fax: +1 212 746 8080, Email: mfg9004@med.cornell.edu

PMCID: PMC8851663 PMID: 34338767

Abstract

Aims

Data suggest that women have worse outcomes than men after coronary artery bypass grafting (CABG), but results have been inconsistent across studies. Due to the large differences in baseline characteristics between sexes, suboptimal risk adjustment due to low-quality data may be the reason for the observed differences. To overcome this limitation, we undertook a systematic review and pooled analysis of high-quality individual patient data from large CABG trials to compare the adjusted outcomes of women and men.

Methods and results

The primary outcome was a composite of all-cause mortality, myocardial infarction (MI), stroke, and repeat revascularization (major adverse cardiac and cerebrovascular events, MACCE). The secondary outcome was all-cause mortality. Multivariable mixed-effect Cox regression was used. Four trials involving 13 193 patients (10 479 males; 2714 females) were included. Over 5 years of follow-up, women had a significantly higher risk of MACCE [adjusted hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04–1.21; P = 0.004] but similar mortality (adjusted HR 1.03, 95% CI 0.94–1.14; P = 0.51) compared to men. Women had higher incidence of MI (adjusted HR 1.30, 95% CI 1.11–1.52) and repeat revascularization (adjusted HR 1.22, 95% CI 1.04–1.43) but not stroke (adjusted HR 1.17, 95% CI 0.90–1.52). The difference in MACCE between sexes was not significant in patients 75 years and older. The use of off-pump surgery and multiple arterial grafting did not modify the difference between sexes.

Conclusions

Women have worse outcomes than men in the first 5 years after CABG. This difference is not significant in patients aged over 75 years and is not affected by the surgical technique.

Keywords: CABG, Sex, Women

Graphical Abstract

graphic file with name ehab504f6.jpg — Risk of major adverse cardiac and cerebrovascular events (all-cause mortality/myocardial infarction/stroke/repeat revascularization) in women vs. men undergoing coronary artery bypass surgery (curves represent unadjusted estimates). HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction.

See page 29 for the editorial comment for this article ‘Why do women do worse after coronary artery bypass grafting?’, by S.A.E. Peters and J. Kluin, https://doi.org/10.1093/eurheartj/ehab617.

Introduction

Coronary artery bypass grafting (CABG) is the most commonly performed cardiac surgery procedure in adults.¹ In the USA, every year ∼200 000 patients undergo CABG and of them between 25% and 30% are women.²

Registries and chart review studies have reported worse early and late outcomes for women compared to men after CABG,³^,⁴ although this finding has not been consistent in all the published series.⁵^,⁶

It is well known that there are key differences in baseline clinical characteristics and in the type and extent of coronary artery disease between men and women referred for CABG.⁵^,⁷ A critical part of any comparison of the CABG outcomes of men and women is the adjustment for this high baseline heterogeneity. Clinical charts and registries have important limitations in terms of granularity and quality of the data, and adjusted estimates based on those datasets have high risk of residual bias and unmeasured confounders. Randomized controlled trials (RCTs) minimize heterogeneity by including only a selected subgroup of the general population and have higher data quality. It is likely that the effectiveness of statistical adjustment and the chances of detecting true sex-related differences are maximized when using RCT-derived data.

However, the proportion of women enrolled in RCTs in cardiovascular medicine is low⁸ and individual trials are underpowered to explore sex-related differences in outcomes.

To overcome these limitations, we performed a systematic review and pooled analysis of the individual patient data from the largest CABG trials to compare postoperative and mid-term outcomes of men and women undergoing CABG surgery after adjusting for prognostically important baseline clinical and surgical characteristics.

Methods

Study protocol

The protocol for the primary and secondary analyses of this study was published a priori.⁹ Ethics approval and participants’ consent were obtained locally by each trial team. The Weill Cornell Medicine Institutional Review Board waived the need for ethics approval for the pooled analysis (protocol #: 20-0902272). The present article was written in accordance with the Individual Patient Data–Preferred Reporting Items for Systematic Reviews and Meta Analyses (IPD-PRISMA) recommendations.

Selection of the trials

A systematic literature search was performed to identify all CABG RCTs (i.e. RCTs where all patients underwent or were expected to undergo CABG). Ovid MEDLINE, Ovid Embase, and Cochrane Trials (Wiley) were searched. The following keywords were used, in combination with the Boolean operator ‘or’: ‘CABG’ and ‘coronary artery bypass’. We decided to include only CABG trials and to exclude trials comparing CABG to other interventions to minimize the potential heterogeneity related to the inclusion of patients who were acceptable candidates for both surgical and non-surgical interventions. To minimize the small-study effect,¹⁰ trials were considered for inclusion only if they had a sample size ≥400 patients. Additional inclusion criteria were that trials: (i) enrolled both men and women, (ii) had a follow-up ≥5 years, and (iii) were written in English. The full search strategy is provided in the Supplementary material online, Appendix.

Two independent investigators performed the eligibility assessment (A.D.F. and M.G.); disagreements were discussed and resolved by consensus. The reference lists of the selected articles were also searched for relevant publications. For overlapping studies, the largest series or the series with the longest follow-up were considered.

Data collection and merging

After identification of eligible trials, the individual trials’ teams were contacted and all agreed to data sharing. Detailed specifications of core minimum de-identified data requirements were provided to each trial team. De-identified data were received by the coordinating centre at Weill Cornell Medicine and checked for quality, completion, and consistency with previous publications. Data were checked for missing values, intra-field data integrity, and inter-field inconsistencies both within each RCT and across the RCTs. Discrepancies were resolved through direct consultation with the individual trials’ teams. Data elements were then consolidated into a final database. The list of the variables collected in each trial is provided in Supplementary material online, Table S1.

Outcomes

The primary outcome was a composite of all-cause mortality, any myocardial infarction (MI), any stroke, and any repeat revascularization (major adverse cardiac and cerebrovascular events, MACCE). The secondary outcome was all-cause mortality. The tertiary outcomes were a composite of death and stroke and operative mortality, defined as death in hospital or within 30 days after surgery. Each individual non-fatal component of the composite outcome was also evaluated separately. For all events, individual trial definitions were used (details are in Supplementary material online, Table S2). All endpoints were compared by sex groups.

Statistical analysis

Baseline and intraoperative characteristics in the two groups were reported as numbers and percentages for categorical variables. For continuous variables normality was assessed using the Shapiro–Wilk test and data reported as means and standard deviations or median and interquartile range as appropriate. Parametric or non-parametric tests were used to compare the two groups, based on normality. Outcomes were reported as frequencies and cumulative incidence. For non-fatal events the cumulative incidence was determined with all-cause mortality as a competing risk using Fine and Gray¹¹ proportional sub-hazards model.

Primary analysis

In the primary analysis, association between treatment and outcomes was estimated using a multivariable mixed-effect Cox regression model, with individual trials as a random effect, and baseline risk factors and surgical techniques as fixed terms. Fixed terms included in the multivariable models were all baseline and operative variables consistently reported across trials, which included: sex, age, diabetes, previous MI, left ventricular ejection fraction (LVEF) <50%, renal insufficiency (serum creatinine >200 μmol/L), body mass index (BMI), New York Heart Association (NYHA) Class III–IV, peripheral vascular disease (PVD), previous stroke, previous percutaneous coronary intervention (PCI), off- or on-pump surgery, number of arterial grafts used (no arterial grafts, SAG: single arterial graft, and MAG: multiple arterial grafts), and total number of grafts. The proportional hazards assumption was verified using Schoenfeld residuals. Missing preoperative data were all <0.1% of the total and were imputed with median or mode values for continuous and categorical variables, respectively (Supplementary material online, Figure S1).

Treatment effects were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analysis and interaction terms were used to investigate the following potential sex effect modifiers in the primary analysis: age, diabetes, previous MI, LVEF, number of grafts, and surgical techniques (off- vs. on-pump and MAG vs. SAG). Non-linearity for the interaction between age and sex was assessed using spline analysis and model χ2 comparison. The cut-off point for age was identified as the intercept between two curves obtained by contrasting adjusted relative risk in the two groups against age.

The effect of sex on the primary endpoint was also calculated using a two-stage approach pooling β coefficients and relative standard error obtained from individual study multivariable Cox regression models. Meta-analytic estimates were obtained using a generic inverse variance method with a random effects model. Trial-level and pooled estimates were reported as HRs and 95% CIs. Heterogeneity across trials was assessed using I² statistics. I² values <25% defined low heterogeneity, 25–50% moderate heterogeneity, and >50% high heterogeneity. Leave-one-out analysis was used to assess the influence of individual trials on the pooled estimate.

Two explanatory analyses not described in the original analysis plan⁹ were added post hoc:

A landmark analysis starting at 30 days after randomization for the primary outcome. This analysis was adjusted using the same method described for the primary analysis.
Age was explored as a modifier of the sex effect for the secondary outcome of all-cause mortality.

Secondary analysis

In the secondary analysis, we investigated the effects of two important CABG surgical techniques (off- vs. on-pump and MAG vs. SAG) on the primary outcome by sex. To account for non-randomized treatment allocation, propensity scores (PS) for each of the two techniques were developed in women and men separately using a gradient boosting machine logistic regression model. Variables included in the PS were age, diabetes, previous MI, LVEF <50%, renal insufficiency, BMI, NYHA Class III–IV, PVD, previous stroke, previous PCI, number of grafts, number of arterial grafts (for the off- vs. on-pump comparison only), and off-pump surgery (for the MAG vs. SAG comparison only). The individual trial identifier was included in the PS model to ensure a balance between subjects from each trial. The treatment effect was evaluated using inverse probability of treatment weighting with ‘average effect of the treatment on treated’. Standardized mean differences were used to assess the balance of covariates between the two treatment groups. A value higher than 0.10 was considered as an indication of residual imbalance.

Supplementary analysis with focus on preoperative left ventricular ejection fraction

To better evaluate the effect of preoperative LVEF on the outcomes by sex, individual patient data from the STICHES (Surgical Treatment of Ischaemic Heart Failure Extension Study) trial¹² (comparing CABG with medical therapy in patients with LVEF ≤35% at 10-year follow-up—see Supplementary material online, Appendix for details of the trial) were obtained through the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung and Blood Institute and added to the database used for the primary analysis. The statistical methods used for this supplementary analysis were the same used in the primary analysis; the only difference was the categorization of preoperative LVEF that in this analysis was performed using a three-, rather than two-, level classification (>50%, 30–50%, and <30%).

Supplementary analysis based on the Open Heart Surgery Registry

To evaluate potential differences in sex effect in a real-world population, we accessed the Open Heart Surgery Registry, the mandatory database of the state of New Jersey, to identify patients who underwent CABG in years 2000–2017. This database is maintained by the New Jersey Department of Health; data are collected by clinical staff at all hospitals performing cardiac surgery in the State. External medical audits verify data quality annually. Long-term clinical outcomes were obtained for individual patients by linking this Open Heart Surgery Registry with the New Jersey Cardiac Catheterization Registry, the New Jersey Discharge Data Collection System, and the New Jersey Vital Statistics death registry, as previously described.¹³^,¹⁴ Patients were followed up until 31 December 2019. The statistical methods used for this supplementary analysis were the same used in the primary analysis.

Supplementary analysis including trial-level data of percutaneous intervention vs. coronary artery bypass grafting

A trial-level meta-analysis was performed pooling aggregate data from the primary analysis and from the CABG arm of the largest trials comparing percutaneous interventions (PCI) and CABG. Details for this analysis are provided in the Supplementary material online, Appendix.

A fixed-order sequential testing method using an alpha level of 0.05 was used to adjust for multiple comparisons in the primary analysis. Significance testing was not performed for the secondary analysis nor for the non-fatal components of the primary composite outcome. For these analyses, only estimates of the association between treatment and outcomes and corresponding 95% CIs were provided, and the results were interpreted as exploratory. All P-values were two-sided. In all the analyses, the male group was used as the reference.

Statistical analyses were performed with R version 3.6.1. and the following packages: coxme, meta, prodlim, twang, Publish.

Results

A total of 1828 studies were identified from the literature search, of which 1225 were screened for eligibility. Four trials met the inclusion criteria [the Arterial Revascularization Trial (ART) the CABG Off or On Pump Revascularization Study (CORONARY), the German Off-Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE), and the Project of Ex-Vivo Vein Graft Engineering via Transfection IV trial (PREVENT IV)].^15–18 The principal investigators of all the trials were contacted and all agreed to share the data (the IPD-PRISMA flowchart is provided in Supplementary material online, Figure S2).

Trials description

In the ART trial,¹⁵ 3102 CABG patients were randomly assigned to bilateral or single internal thoracic artery grafting (1548 vs. 1554 patients, respectively). Patients were enrolled from 2004 to 2007 at 28 hospitals from 4 continents and a total of 7 countries. At 10-year follow-up, the authors found no significant between-group difference in the rate of death from any cause (HR 0.96, 95% CI 0.82–1.12) and in the composite outcome of death, MI, or stroke (HR 0.90, 95% CI 0.79–1.03).

In the CORONARY trial,¹⁶ 4752 patients were randomly assigned to undergo off-pump or on-pump CABG (2375 vs. 2377 patients, respectively). Patients were enrolled from 2006 to 2011 at 79 centres from 4 continents and 19 countries. At 4.8-year follow-up, the rate of the composite outcome of death, stroke, MI, renal failure, or repeat revascularization was similar between groups (HR 0.98, 95% CI 0.87–1.10).

In the GOPCABE trial,¹⁷ 2539 patients aged ≥75 years were randomly assigned to undergo off-pump or on-pump CABG (1271 vs. 1268 patients, respectively). Patients were enrolled from 2008 to 2011 at 12 centres in Germany. At 5-year follow-up, survival rates (HR 1.03, 95% CI 0.89–1.19) and the combined outcome of death, MI, and repeat revascularization (HR 1.03, 95% CI 0.89–1.18) were similar in the two groups.

In the PREVENT IV trial,¹⁸ 3014 patients undergoing primary CABG surgery with at least two planned saphenous vein grafts were randomly assigned to undergo ex vivo vein graft treatment with either edifoligide or placebo (1508 vs. 1506 patients, respectively). Patients were enrolled from 2002 to 2003 at 107 sites in the USA. At 5-year follow-up, the rates of the adjusted composite outcome of death, MI, or revascularization (HR 1.15, 95% CI 1.00–1.31) and of death or MI (HR 1.21, 95% CI 1.03–1.43) were significantly higher in patients receiving saphenous vein grafts with multiple vs. single distal targets.

Baseline patients’ characteristics and operative outcomes in the individual trials are provided in Supplementary material online, Tables S3 and S4, respectively.

Overall, 13 193 patients (10 479 men and 2714 women) were included. Baseline and operative characteristics from the pooled sample are summarized in Table 1. The female cohort was older and more symptomatic and had higher prevalence of comorbidities (diabetes, hypertension, PVD, previous stroke) compared to the male cohort. Intraoperatively, the rate of off-pump procedures was similar between women and men; women received a significantly lower number of grafts and arterial grafts.

Table 1.

Baseline and operative characteristics of the patients in the pooled sample

	Overall (n = 13 193)	Males (n = 10 479)	Females (n = 2714)	P-value
Age (years), mean (SD)	67.6 (9.5)	67.0 (9.5)	69.96 (9.4)	<0.001
Renal insufficiency, n (%)	270 (2.0)	215 (2.1)	55 (2.0)	0.99
Diabetes, n (%)	4418 (33.5)	3391 (32.4)	1027 (37.8)	<0.001
Previous MI, n (%)	5033 (38.1)	4070 (38.8)	963 (35.5)	0.001
LVEF <50%, n (%)	7196 (54.5)	5860 (55.9)	1336 (49.2)	<0.001
BMI (kg/m²), mean (SD)	27.9 (4.7)	27.77 (4.5)	28.51 (5.2)	<0.001
NYHA Class III–IV, n (%)	3700 (28.0)	2758 (26.3)	942 (34.7)	<0.001
Hypertension, n (%)	8159 (61.8)	6528 (62.3)	1631 (60.1)	<0.001
Hyperlipidaemia, n (%)	8722 (66.1)	7169 (68.4)	1553 (57.2)	0.10
COPD, n (%)	796 (6.0)	627 (5.9)	169 (6.2)	0.92
PVD, n (%)	1710 (13.0)	1320 (12.6)	390 (14.4)	0.016
Previous stroke, n (%)	1160 (8.8)	880 (8.4)	280 (10.3)	0.002
Previous PCI, n (%)	2239 (17.0)	1766 (16.9)	473 (17.4)	0.50
Off-pump, n (%)	5324 (40.4)	4213 (40.2)	1111 (40.9)	0.50
Number of grafts, mean (SD)	3.1 (0.9)	3.2 (0.9)	2.9 (0.9)	<0.001
Number of arterial grafts, n (%)				<0.001
0	598 (4.5)	423 (4.0)	175 (6.4)
1	9068 (68.7)	7119 (67.9)	1949 (71.8)
≥2	3527 (26.7)	2937 (28.0)	590 (21.7)

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BMI, body mass index; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; SD, standard deviation.

The mean follow-up time was 5.3 ± 2.4 and 5.8 ± 2.5 years in the female and male cohorts, respectively.

Primary analysis

Operative results are summarized in Table 2; operative mortality was similar for women and men [2.3% vs. 1.7%, adjusted odds ratio (OR) 1.27, 95% CI 0.94–1.72]. Women had a higher incidence of perioperative MI (6.3% vs. 5.2%, adjusted OR 1.27, 95% CI 1.06–1.53), a lower incidence of atrial fibrillation (15.2% vs. 18.5%, adjusted OR 0.82, 95% CI 0.73–0.94), and similar rates of stroke, repeat revascularization, reoperation for bleeding, need for renal replacement therapy, and mediastinitis compared to men.

Table 2.

Operative outcomes in the pooled sample

	Overall (n = 13 193), n (%)	Males (n = 10 479), n (%)	Females (n = 2714), n (%)	Adjusted OR^a (95% CI)
MACCE	1075 (8.1)	807 (7.7)	268 (9.9)	1.28 (1.10–1.49)
Mortality^b	243 (1.8)	181 (1.7)	62 (2.3)	1.27 (0.94–1.72)
MI	714 (5.4)	542 (5.2)	172 (6.3)	1.27 (1.06–1.53)
Stroke	174 (1.3)	125 (1.2)	49 (1.8)	1.34 (0.95–1.90)
Repeat revascularization	61 (0.5)	44 (0.4)	17 (0.6)	1.29 (0.72–2.33)
Reoperation for bleeding	394 (3.0)	321 (3.1)	73 (2.7)	0.84 (0.65–1.10)
Renal replacement therapy	378 (2.9)	293 (2.8)	85 (3.1)	1.18 (0.89–1.57)
Postoperative atrial fibrillation	2350 (17.8)	1937 (18.5)	413 (15.2)	0.82 (0.73–0.94)
Mediastinitis	89 (0.7)	70 (0.7)	19 (0.7)	0.98 (0.58–1.66)

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BMI, body mass index; CI, confidence interval; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; NYHA, New York Heart Association; OR, odds ratio; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

Adjusted using a multivariable regression model with individual trials as a random effect including age, diabetes, previous MI, LVEF <50%, renal insufficiency (serum creatinine >200 μmol/L), BMI, NYHA Class III–IV, PVD, previous stroke, previous PCI, off-pump surgery, number of arterial grafts used (no arterial grafts, single arterial grafts, and multiple arterial grafts), and total number of grafts.

Unadjusted OR (95% CI): 1.25 (0.93–1.69).

Over 5 years of follow-up, women had a significantly higher risk of MACCE compared to men (adjusted HR 1.12, 95% CI 1.04–1.21, P = 0.004) (Table 3 and Graphical abstract) but similar risk of all-cause mortality (adjusted HR 1.03, 95% CI 0.94–1.14, P = 0.51) (Figure 1A) and composite of all-cause mortality and stroke (adjusted HR 1.04, 95% CI 0.95–1.14) (Figure 1B).

Table 3.

Results of the analysis for the primary and secondary outcomes and the non-fatal individual components of the primary outcome

	Overall (n = 13 193)	Males (n = 10 479)	Females (n = 2714)	Unadjusted HR (95% CI)	P-value (unadjusted comparison)	Adjusted HR^a (95% CI)	P-value (adjusted comparison)
Follow-up (years), mean (SD)	5.7 (2.5)	5.8 (2.5)	5.3 (2.4)	—	—	—	—
MACCE, n (%)	3924 (29.7)	3012 (28.7)	912 (33.6)	1.19 (1.11–1.29)	<0.001	1.12 (1.04–1.21)	0.004
All-cause mortality, n (%)	2375 (18.0)	1817 (17.3)	558 (20.6)	1.11 (1.00–1.22)	0.04	1.03 (0.94–1.14)	0.51
All-cause mortality/stroke, n (%)	607 (22.4)	1987 (19.0)	2594 (19.7)	1.11 (1.01–1.22)	0.03	1.04 (0.95–1.14)	—
MI, n (%)	924 (7.0)	703 (6.7)	221 (8.1)	1.33 (1.14–1.55)	—	1.30 (1.11–1.52)	—
Stroke, n (%)	350 (2.7)	270 (2.6)	80 (2.9)	1.26 (0.98–1.62)	—	1.17 (0.90–1.52)	—
Repeat revascularization, n (%)	940 (7.1)	732 (7.0)	208 (7.7)	1.25 (1.07–1.46)	—	1.22 (1.04–1.43)	—

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BMI, body mass index; CI, confidence interval; HR, hazard ratio; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

Adjusted for age, diabetes, previous MI, LVEF <50%, renal insufficiency (serum creatinine >200 μmol/L), BMI, NYHA Class III–IV, PVD, previous stroke, previous PCI, off-pump surgery, number of arterial grafts used (no arterial grafts, single arterial grafts, and multiple arterial grafts), and total number of grafts.

Risk of (A) all-cause mortality and (B) all-cause mortality/stroke in women vs. men undergoing coronary artery bypass surgery (curves represent unadjusted estimates). HR, hazard ratio.

When analysing the non-fatal individual components of the composite outcome, women had higher incidence of MI (adjusted HR 1.30, 95% CI 1.11–1.52) and repeat revascularization (adjusted HR 1.22, 95% CI 1.04–1.43), but not of stroke (adjusted HR 1.17, 95% CI 0.90–1.52) (Table 3 and Figure 2).

Risk of (A) myocardial infarction, (B) stroke, and (C) repeat revascularization in women vs. men undergoing coronary artery bypass surgery (curves represent unadjusted estimates). HR, hazard ratio.

Results of the analysis on sex effect modifiers are provided in Figure 3. Age had a significant interaction (spline 3 knots) with sex on the long-term risk of MACCE (Figure 4). Age 75 was the cut-off for equipoise between women and men (adjusted HR 1.29, 95% CI 1.17–1.43 for age <75 years vs. adjusted HR 0.94, 95% CI 0.83–1.05 for age ≥75; interaction P < 0.001). Off- vs. on-pump surgery (interaction P = 0.22), use of MAG vs. SAG (interaction P = 0.39), diabetes (interaction P = 0.09), prior MI (interaction P = 0.26), and LVEF <50% (interaction P = 0.07) did not modify the effect of sex on MACCE.

Sex effect modifiers in the primary analysis. CI, confidence interval; HR, hazard ratio; MAG, multiple arterial grafts; MI, myocardial infarction.

Association of sex across age groups with major adverse cardiac and cerebrovascular events (all-cause mortality/myocardial infarction/stroke/repeat revascularization).

Age had a similar modifier effect on all-cause mortality with the same 75 years cut-off (adjusted HR 1.18, 95% CI 1.02–1.36 for age <75; adjusted HR 0.90, 95% CI 0.79–1.03 for age ≥75; interaction P < 0.001) (Supplementary material online, Figure S3).

In the landmark analysis starting at 30 days from randomization, female sex was not associated with an increased risk of MACCE (adjusted HR 1.06, 95% CI 0.97–1.16) (Figure 5).

Landmark analysis for major adverse cardiac and cerebrovascular events (all-cause mortality/myocardial infarction/stroke/repeat revascularization) at 30 days (curves represent unadjusted estimates; time starts at 30 days after randomization). HR, hazard ratio; MI, myocardial infarction.

The pooled estimate for the primary endpoint from the two-stage analysis was consistent with the main analysis (Supplementary material online, Figures S4 and S5).

Secondary analysis

Propensity scores-weighting achieved good balance between off- vs. on-pump and MAG vs. SAG groups for both sexes (Supplementary material online, Tables S5–S8). The risk of MACCE was similar after off- vs. on-pump surgery for women (adjusted HR 0.94, 95% CI 0.81–1.08) and men (adjusted HR 1.02, 95% CI 0.94–1.10) (Supplementary material online, Figure S6A and B). When compared to SAG, MAG was associated with a reduction in the risk of MACCE in men (adjusted HR 0.86, 95% CI 0.78–0.95) but not in women (adjusted HR 0.97, 95% CI 0.80–1.17) (Supplementary material online, Figure S6C and D).

Supplementary analyses

The results of the analysis including the STICHES trial were consistent with the primary analysis (adjusted HR for MACCE 1.12, 95% CI 1.04–1.21; adjusted HR for mortality 1.03, 95% CI 0.94–1.14) (Supplementary material online, Table S9 and Figure S7). Preoperative LVEF was a significant sex effect modifier; women with preoperative LVEF <30% had lower risk of MACCE compared to men, while the opposite was seen among patients with LVEF >30% (Supplementary material online, Figure S8).

The results of the analysis of the Open Heart Surgery Registry were consistent with the primary analysis (HR for MACCE 1.15, 95% CI 1.13–1.15, HR for mortality 1.04, 95% CI 1.004–1.07) (Supplementary material online, Table S10 and Figure S9).

In the trial-level meta-analysis including the PCI vs. CABG trials, women had higher risk of MACCE and mortality than men (HR 1.09, 95% CI 0.85–1.39 and HR 1.41, 95% CI 1.04–1.92, respectively) (Supplementary material online, Figure S10).

Discussion

In this analysis of 13 193 patients (2714 women) followed for a mean of 5 years, we found that, after CABG, women have higher adjusted incidence of adverse cardiac and cerebrovascular events, but similar mortality compared to men. The higher incidence of MACCE is mostly driven by a higher rate of MI and repeat revascularization.

A new and important finding is that the difference between sexes is inversely associated with age and disappears at 75 years. Coronary artery disease in young women has distinct pathophysiological features and outcomes; e.g. women more often have coronary dissection, microvascular dysfunction, spasm, or myocardial bridges than men and have higher mortality after acute coronary events.⁷^,¹⁹^,²⁰ In a large registry study including 51 187 patients (15 178 women),²¹ Vaccarino et al. found that women younger than 50 years had two times higher adjusted operative mortality after CABG compared to men of the same age range and that the difference in operative outcomes between sexes decreased with increasing age. It is possible that CABG is less effective in a younger female population, but this has not been investigated in details.

Another important finding is that preoperative LVEF was a significant sex effect modifier; while women with preoperative LVEF >30% had increased risk of MACCE compared to men, the opposite was true among patients with LVEF <30%.

We have also found that women have a higher risk of perioperative MI after CABG and in the landmark analysis excluding the early postoperative period, the difference in outcome between groups was clearly attenuated. Native coronary arteries and bypass conduits in women are generally smaller,²²^,²³ and there is in vitro evidence that they may have a higher tendency to spasm compared to men.²⁴^,²⁵ It is possible that the CABG procedure is technically more complex in women and that graft failure due to technical reasons may have played a role in the observed differences. The higher rate of perioperative MI may have also affected the mid-term outcomes.²⁶ The tendency to spasm⁷^,¹⁹ and the technical complexity are likely increased in younger women and this may explain the reported association of age with the difference in outcomes between sexes. These findings are hypothesis generating and require further investigation.

In the only published study-level meta-analysis investigating the impact of sex on outcomes following CABG, Alam et al.²⁷ pooled data from 20 studies and 966 492 patients (277 783 women) and found that female sex was associated with higher adjusted risk of operative mortality and that the mortality differences between sexes persisted at 5-year follow-up (OR 1.77, 95% CI 1.67–1.88 and OR 1.14, 95% CI 1.08–1.20, respectively).

Our analysis also suggests that variations in CABG surgical technique (off- vs. on-pump surgery and use of MAG vs. SAG) do not improve the outcomes of women and do not reduce the difference between sexes. This finding highlights the need to explore new modifications of the surgical technique or of postoperative protocols to improve CABG outcomes in women.

The secondary analyses comparing the effect of different surgical techniques in the two sexes suffer from inevitable treatment allocation and expertise biases²⁸ and were designed to provide exploratory data on the relative difference in treatment effect by sex, not on the absolute efficacy of the four techniques analysed.

Off-pump CABG was not associated with significant changes in outcomes both in men and women. This is concordant with the results of RCTs and observational studies limited to surgeons with experience in the off-pump technique.¹⁶^,²⁹ In contrast, MAG was associated with better outcomes in men, but not in women. The available observational evidence on the use of MAG in women is conflicting, with some studies suggesting and others refuting a clinical benefit for women who receive more than one arterial graft for CABG.^30–34 Data suggest that the potential benefit of MAG may be lost in higher risk patients,¹³^,³⁵ and this may explain why women, who have worse baseline risk profile, may not benefit as much as men from MAG. Overall, our analysis suggests that a sex-related difference in the effect of MAG may exist and underlines the need for new and better evidence on this topic.

Several limitations of this study must be acknowledged. Outcome definitions and event adjudication were not standardized in the included trials, although all used an independent adjudication committee. It is likely that there was substantial heterogeneity in surgical techniques and postoperative protocols between the included trials and the individual participating sites. Finally, the cardiovascular event rate in CABG patients increases substantially after the fifth postoperative year and longer-term data are needed to confirm the present results (e.g. the benefit of MAG may become apparent in women with longer follow-up). On the other hand, results were solid in multiple sensitivity and supplementary analyses, even when including aggregate data from other trials and when repeating the analysis in a large real-world registry.

In conclusion, in a pooled analysis of four large CABG trials, we have found that, in the first 5 years after surgery, women have worse cardiac and cerebrovascular outcomes than men. The difference in outcomes between the sexes is not evident after 75 years of age and is significantly affected by preoperative LVEF, but not by variations in the surgical technique used. Women have a higher risk of perioperative MI that may be due to technical factors and may be one of the reasons for the difference in mid-term outcomes.

Further effort in understanding and improving the outcome of women (and particularly younger women) undergoing CABG are needed.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This project was funded by the Department of Cardiothoracic Surgery of Weill Cornell Medicine in New York. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Conflict of interest: none declared.

Ethical approval

Ethics approval and participant consent was obtained locally by each trial team. The Weill Cornell Medicine Institutional Review Board waived the need for ethics approval for the pooled analysis (protocol #: 20-0902272).

Data availability

Data collected for the study will be made available by the corresponding author upon reasonable request after publication.

Supplementary Material

ehab504_Supplementary_Data

Click here for additional data file.^{(2.3MB, docx)}

References

1. McDermott KW, Freeman WJ, Elixhauser A. Overview of operating room procedures during inpatient stays in U.S. hospitals, 2014: Statistical Brief #233 [Internet]. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Quality (US); 2006. http://www.ncbi.nlm.nih.gov/books/NBK487976/ (15 August 2020). [PubMed]
2. ElBardissi AW, Aranki SF, Sheng S, O'Brien SM, Greenberg CC, Gammie JS.. Trends in isolated coronary artery bypass grafting: an analysis of the Society of Thoracic Surgeons adult cardiac surgery database. J Thorac Cardiovasc Surg 2012;143:273–281. [DOI] [PubMed] [Google Scholar]
3. Alam M, Lee V-V, Elayda MA, Shahzad SA, Yang EY, Nambi V, Jneid H, Pan W, Coulter S, Wilson JM, Ramanathan KB, Ballantyne CM, Virani SS.. Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis. Int J Cardiol 2013;167:180–184. [DOI] [PubMed] [Google Scholar]
4. Kasirajan V, Wolfe LG, Medina A.. Adverse influence of female gender on outcomes after coronary bypass surgery: a propensity matched analysis. Interact CardioVasc Thorac Surg 2009;8:408–411. [DOI] [PubMed] [Google Scholar]
5. Koch CG, Khandwala F, Nussmeier N, Blackstone EH.. Gender and outcomes after coronary artery bypass grafting: a propensity-matched comparison. J Thorac Cardiovasc Surg 2003;126:2032–2043. [DOI] [PubMed] [Google Scholar]
6. Guru V, Fremes SE, Austin PC, Blackstone EH, Tu JV.. Gender differences in outcomes after hospital discharge from coronary artery bypass grafting. Circulation 2006;113:507–516. [DOI] [PubMed] [Google Scholar]
7. Yahagi K, Davis HR, Arbustini E, Virmani R.. Sex differences in coronary artery disease: pathological observations. Atherosclerosis 2015;239:260–267. [DOI] [PubMed] [Google Scholar]
8. Feldman S, Ammar W, Lo K, Trepman E, van Zuylen M, Etzioni O.. Quantifying sex bias in clinical studies at scale with automated data extraction. JAMA Netw Open 2019;2:e196700. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Gaudino M, Alexander JH, Egorova N, Kurlansky P, Lamy A, Bakaeen F, Hameed I, Di Franco A, Demetres M, Robinson NB, Chikwe J, Lawton JS, Devereaux PJ, Taggart DP, Flather M, Reents W, Boening A, Diegeler A, Girardi LN, Fremes SE, Benedetto U.. Sex-related differences in outcomes after coronary artery bypass surgery—a patient-level pooled analysis of randomized controlled trials: rationale and study protocol. J Card Surg 2020;35:2754–2758. [DOI] [PubMed] [Google Scholar]
10. Sterne JA, Gavaghan D, Egger M.. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119–1129. [DOI] [PubMed] [Google Scholar]
11. Fine J, Gray R.. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509. [Google Scholar]
12. Velazquez EJ, Lee KL, Jones RH, Al-Khalidi HR, Hill JA, Panza JA, Michler RE, Bonow RO, Doenst T, Petrie MC, Oh JK, She L, Moore VL, Desvigne-Nickens P, Sopko G, Rouleau JL, Stiches I.. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511–1520. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Chikwe J, Sun E, Hannan EL, Itagaki S, Lee T, Adams DH, Egorova NN.. Outcomes of second arterial conduits in patients undergoing multivessel coronary artery bypass graft surgery. J Am Coll Cardiol 2019;74:2238–2248. [DOI] [PubMed] [Google Scholar]
14. Chikwe J, Lee T, Itagaki S, Adams DH, Egorova NN.. Long-term outcomes after off-pump versus on-pump coronary artery bypass grafting by experienced surgeons. J Am Coll Cardiol 2018;72:1478–1486. [DOI] [PubMed] [Google Scholar]
15. Taggart DP, Benedetto U, Gerry S, Altman DG, Gray AM, Lees B, Gaudino M, Zamvar V, Bochenek A, Buxton B, Choong C, Clark S, Deja M, Desai J, Hasan R, Jasinski M, O'Keefe P, Moraes F, Pepper J, Seevanayagam S, Sudarshan C, Trivedi U, Wos S, Puskas J, Flather M; Arterial Revascularization Trial Investigators. Bilateral versus single internal-thoracic-artery grafts at 10 years. N Engl J Med 2019;380:437–446. [DOI] [PubMed] [Google Scholar]
16. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Straka Z, Piegas LS, Avezum A, Akar AR, Lanas Zanetti F, Jain AR, Noiseux N, Padmanabhan C, Bahamondes J-C, Novick RJ, Tao L, Olavegogeascoechea PA, Airan B, Sulling T-A, Whitlock RP, Ou Y, Gao P, Pettit S, Yusuf S; CORONARY Investigators. Five-year outcomes after off-pump or on-pump coronary-artery bypass grafting. N Engl J Med 2016;375:2359–2368. [DOI] [PubMed] [Google Scholar]
17. Diegeler A, Börgermann J, Kappert U, Hilker M, Doenst T, Böning A, Albert M, Färber G, Holzhey D, Conradi L, Rieß F-C, Veeckmann P, Minorics C, Zacher M, Reents W.. Five-Year outcome after off-pump or on-pump coronary artery bypass grafting in elderly patients. Circulation 2019;139:1865–1871. [DOI] [PubMed] [Google Scholar]
18. Mehta RH, Ferguson TB, Lopes RD, Hafley GE, Mack MJ, Kouchoukos NT, Gibson CM, Harrington RA, Califf RM, Peterson ED, Alexander JH; Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV Investigators. Saphenous vein grafts with multiple versus single distal targets in patients undergoing coronary artery bypass surgery: one-year graft failure and five-year outcomes from the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV trial. Circulation 2011;124:280–288. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Mehilli J, Presbitero P.. Coronary artery disease and acute coronary syndrome in women. Heart Br Card Soc 2020;106:487–492. [DOI] [PubMed] [Google Scholar]
20. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM.. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 1999;341:217–225. [DOI] [PubMed] [Google Scholar]
21. Vaccarino V, Abramson JL, Veledar E, Weintraub WS.. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 2002;105:1176–1181. [DOI] [PubMed] [Google Scholar]
22. Sheifer SE, Canos MR, Weinfurt KP, Arora UK, Mendelsohn FO, Gersh BJ, Weissman NJ.. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000;139:649–653. [DOI] [PubMed] [Google Scholar]
23. Lawton JS, Barner HB, Bailey MS, Guthrie TJ, Moazami N, Pasque MK, Moon MR, Damiano RJ.. Radial artery grafts in women: utilization and results. Ann Thorac Surg 2005;80:559–563. [DOI] [PubMed] [Google Scholar]
24. Dignan RJ, Yeh T, Dyke CM, Lutz HA, Wechsler AS.. The influence of age and sex on human internal mammary artery size and reactivity. Ann Thorac Surg 1992;53:792–797. [DOI] [PubMed] [Google Scholar]
25. Lamin V, Jaghoori A, Jakobczak R, Stafford I, Heresztyn T, Worthington M, Edwards J, Viana F, Stuklis R, Wilson DP, Beltrame JF.. Mechanisms responsible for serotonin vascular reactivity sex differences in the internal mammary artery. J Am Heart Assoc 2018;7:e007126. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Gregson J, Stone GW, Ben-Yehuda O, Redfors B, Kandzari DE, Morice M-C, Leon MB, Kosmidou I, Lembo NJ, Brown WM, Karmpaliotis D, Banning AP, Pomar J, Sabaté M, Simonton CA, Dressler O, Kappetein AP, Sabik JF, Serruys PW, Pocock SJ.. Implications of alternative definitions of peri-procedural myocardial infarction after coronary revascularization. J Am Coll Cardiol 2020;76:1609–1621. [DOI] [PubMed] [Google Scholar]
27. Alam M, Bandeali SJ, Kayani WT, Ahmad W, Shahzad SA, Jneid H, Birnbaum Y, Kleiman NS, Coselli JS, Ballantyne CM, Lakkis N, Virani SS.. Comparison by meta-analysis of mortality after isolated coronary artery bypass grafting in women versus men. Am J Cardiol 2013;112:309–317. [DOI] [PubMed] [Google Scholar]
28. Gaudino M, Di Franco A, Rahouma M, Tam DY, Iannaccone M, Deb S, D'Ascenzo F, Abouarab AA, Girardi LN, Taggart DP, Fremes SE.. Unmeasured confounders in observational studies comparing bilateral versus single internal thoracic artery for coronary artery bypass grafting: a meta-analysis. J Am Heart Assoc 2018;7:e008010. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Kirmani BH, Holmes MV, Muir AD.. Long-term survival and freedom from reintervention after off-pump coronary artery bypass grafting: a propensity-matched study. Circulation 2016;134:1209–1220. [DOI] [PubMed] [Google Scholar]
30. Schwann TA, Engoren M, Bonnell M, Clancy C, Habib RH.. Comparison of late coronary artery bypass graft survival effects of radial artery versus saphenous vein grafting in male and female patients. Ann Thorac Surg 2012;94:1485–1491. [DOI] [PubMed] [Google Scholar]
31. Dimitrova KR, Hoffman DM, Geller CM, Ko W, Lucido DJ, Dincheva GR, Tranbaugh RF.. Radial artery grafting in women improves 15-year survival. J Thorac Cardiovasc Surg 2013;146:1467–1473. [DOI] [PubMed] [Google Scholar]
32. Kurlansky PA, Traad EA, Dorman MJ, Galbut DL, Zucker M, Ebra G.. Bilateral internal mammary artery grafting reverses the negative influence of gender on outcomes of coronary artery bypass grafting surgery. Eur J Cardiothorac Surg 2013;44:54–63. [DOI] [PubMed] [Google Scholar]
33. Vrancic JM, Navia DO, Espinoza JC, Piccinini F, Camporrotondo M, Benzadon M, Dorsa A.. Is sex a risk factor for death in patients with bilateral internal thoracic artery grafts? J Thorac Cardiovasc Surg 2019;158:1345–1353.e1. [DOI] [PubMed] [Google Scholar]
34. Kurlansky PA, Traad EA, Galbut DL, Zucker M, Ebra G.. Efficacy of single versus bilateral internal mammary artery grafting in women: a long-term study. Ann Thorac Surg 2001;71:1949–1957; discussion 1957–1958. [DOI] [PubMed] [Google Scholar]
35. Benedetto U, Amrani M, Raja SG; Harefield Cardiac Outcomes Research Group. Guidance for the use of bilateral internal thoracic arteries according to survival benefit across age groups. J Thorac Cardiovasc Surg 2014;148:2706–2711. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ehab504_Supplementary_Data

Click here for additional data file.^{(2.3MB, docx)}

Data Availability Statement

Data collected for the study will be made available by the corresponding author upon reasonable request after publication.

[ehab504-B1] 1. McDermott KW, Freeman WJ, Elixhauser A. Overview of operating room procedures during inpatient stays in U.S. hospitals, 2014: Statistical Brief #233 [Internet]. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Quality (US); 2006. http://www.ncbi.nlm.nih.gov/books/NBK487976/ (15 August 2020). [PubMed]

[ehab504-B2] 2. ElBardissi AW, Aranki SF, Sheng S, O'Brien SM, Greenberg CC, Gammie JS.. Trends in isolated coronary artery bypass grafting: an analysis of the Society of Thoracic Surgeons adult cardiac surgery database. J Thorac Cardiovasc Surg 2012;143:273–281. [DOI] [PubMed] [Google Scholar]

[ehab504-B3] 3. Alam M, Lee V-V, Elayda MA, Shahzad SA, Yang EY, Nambi V, Jneid H, Pan W, Coulter S, Wilson JM, Ramanathan KB, Ballantyne CM, Virani SS.. Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis. Int J Cardiol 2013;167:180–184. [DOI] [PubMed] [Google Scholar]

[ehab504-B4] 4. Kasirajan V, Wolfe LG, Medina A.. Adverse influence of female gender on outcomes after coronary bypass surgery: a propensity matched analysis. Interact CardioVasc Thorac Surg 2009;8:408–411. [DOI] [PubMed] [Google Scholar]

[ehab504-B5] 5. Koch CG, Khandwala F, Nussmeier N, Blackstone EH.. Gender and outcomes after coronary artery bypass grafting: a propensity-matched comparison. J Thorac Cardiovasc Surg 2003;126:2032–2043. [DOI] [PubMed] [Google Scholar]

[ehab504-B6] 6. Guru V, Fremes SE, Austin PC, Blackstone EH, Tu JV.. Gender differences in outcomes after hospital discharge from coronary artery bypass grafting. Circulation 2006;113:507–516. [DOI] [PubMed] [Google Scholar]

[ehab504-B7] 7. Yahagi K, Davis HR, Arbustini E, Virmani R.. Sex differences in coronary artery disease: pathological observations. Atherosclerosis 2015;239:260–267. [DOI] [PubMed] [Google Scholar]

[ehab504-B8] 8. Feldman S, Ammar W, Lo K, Trepman E, van Zuylen M, Etzioni O.. Quantifying sex bias in clinical studies at scale with automated data extraction. JAMA Netw Open 2019;2:e196700. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ehab504-B9] 9. Gaudino M, Alexander JH, Egorova N, Kurlansky P, Lamy A, Bakaeen F, Hameed I, Di Franco A, Demetres M, Robinson NB, Chikwe J, Lawton JS, Devereaux PJ, Taggart DP, Flather M, Reents W, Boening A, Diegeler A, Girardi LN, Fremes SE, Benedetto U.. Sex-related differences in outcomes after coronary artery bypass surgery—a patient-level pooled analysis of randomized controlled trials: rationale and study protocol. J Card Surg 2020;35:2754–2758. [DOI] [PubMed] [Google Scholar]

[ehab504-B10] 10. Sterne JA, Gavaghan D, Egger M.. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000;53:1119–1129. [DOI] [PubMed] [Google Scholar]

[ehab504-B11] 11. Fine J, Gray R.. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509. [Google Scholar]

[ehab504-B12] 12. Velazquez EJ, Lee KL, Jones RH, Al-Khalidi HR, Hill JA, Panza JA, Michler RE, Bonow RO, Doenst T, Petrie MC, Oh JK, She L, Moore VL, Desvigne-Nickens P, Sopko G, Rouleau JL, Stiches I.. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511–1520. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ehab504-B13] 13. Chikwe J, Sun E, Hannan EL, Itagaki S, Lee T, Adams DH, Egorova NN.. Outcomes of second arterial conduits in patients undergoing multivessel coronary artery bypass graft surgery. J Am Coll Cardiol 2019;74:2238–2248. [DOI] [PubMed] [Google Scholar]

[ehab504-B14] 14. Chikwe J, Lee T, Itagaki S, Adams DH, Egorova NN.. Long-term outcomes after off-pump versus on-pump coronary artery bypass grafting by experienced surgeons. J Am Coll Cardiol 2018;72:1478–1486. [DOI] [PubMed] [Google Scholar]

[ehab504-B15] 15. Taggart DP, Benedetto U, Gerry S, Altman DG, Gray AM, Lees B, Gaudino M, Zamvar V, Bochenek A, Buxton B, Choong C, Clark S, Deja M, Desai J, Hasan R, Jasinski M, O'Keefe P, Moraes F, Pepper J, Seevanayagam S, Sudarshan C, Trivedi U, Wos S, Puskas J, Flather M; Arterial Revascularization Trial Investigators. Bilateral versus single internal-thoracic-artery grafts at 10 years. N Engl J Med 2019;380:437–446. [DOI] [PubMed] [Google Scholar]

[ehab504-B16] 16. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Straka Z, Piegas LS, Avezum A, Akar AR, Lanas Zanetti F, Jain AR, Noiseux N, Padmanabhan C, Bahamondes J-C, Novick RJ, Tao L, Olavegogeascoechea PA, Airan B, Sulling T-A, Whitlock RP, Ou Y, Gao P, Pettit S, Yusuf S; CORONARY Investigators. Five-year outcomes after off-pump or on-pump coronary-artery bypass grafting. N Engl J Med 2016;375:2359–2368. [DOI] [PubMed] [Google Scholar]

[ehab504-B17] 17. Diegeler A, Börgermann J, Kappert U, Hilker M, Doenst T, Böning A, Albert M, Färber G, Holzhey D, Conradi L, Rieß F-C, Veeckmann P, Minorics C, Zacher M, Reents W.. Five-Year outcome after off-pump or on-pump coronary artery bypass grafting in elderly patients. Circulation 2019;139:1865–1871. [DOI] [PubMed] [Google Scholar]

[ehab504-B18] 18. Mehta RH, Ferguson TB, Lopes RD, Hafley GE, Mack MJ, Kouchoukos NT, Gibson CM, Harrington RA, Califf RM, Peterson ED, Alexander JH; Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV Investigators. Saphenous vein grafts with multiple versus single distal targets in patients undergoing coronary artery bypass surgery: one-year graft failure and five-year outcomes from the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV trial. Circulation 2011;124:280–288. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ehab504-B19] 19. Mehilli J, Presbitero P.. Coronary artery disease and acute coronary syndrome in women. Heart Br Card Soc 2020;106:487–492. [DOI] [PubMed] [Google Scholar]

[ehab504-B20] 20. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM.. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 1999;341:217–225. [DOI] [PubMed] [Google Scholar]

[ehab504-B21] 21. Vaccarino V, Abramson JL, Veledar E, Weintraub WS.. Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women. Circulation 2002;105:1176–1181. [DOI] [PubMed] [Google Scholar]

[ehab504-B22] 22. Sheifer SE, Canos MR, Weinfurt KP, Arora UK, Mendelsohn FO, Gersh BJ, Weissman NJ.. Sex differences in coronary artery size assessed by intravascular ultrasound. Am Heart J 2000;139:649–653. [DOI] [PubMed] [Google Scholar]

[ehab504-B23] 23. Lawton JS, Barner HB, Bailey MS, Guthrie TJ, Moazami N, Pasque MK, Moon MR, Damiano RJ.. Radial artery grafts in women: utilization and results. Ann Thorac Surg 2005;80:559–563. [DOI] [PubMed] [Google Scholar]

[ehab504-B24] 24. Dignan RJ, Yeh T, Dyke CM, Lutz HA, Wechsler AS.. The influence of age and sex on human internal mammary artery size and reactivity. Ann Thorac Surg 1992;53:792–797. [DOI] [PubMed] [Google Scholar]

[ehab504-B25] 25. Lamin V, Jaghoori A, Jakobczak R, Stafford I, Heresztyn T, Worthington M, Edwards J, Viana F, Stuklis R, Wilson DP, Beltrame JF.. Mechanisms responsible for serotonin vascular reactivity sex differences in the internal mammary artery. J Am Heart Assoc 2018;7:e007126. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ehab504-B26] 26. Gregson J, Stone GW, Ben-Yehuda O, Redfors B, Kandzari DE, Morice M-C, Leon MB, Kosmidou I, Lembo NJ, Brown WM, Karmpaliotis D, Banning AP, Pomar J, Sabaté M, Simonton CA, Dressler O, Kappetein AP, Sabik JF, Serruys PW, Pocock SJ.. Implications of alternative definitions of peri-procedural myocardial infarction after coronary revascularization. J Am Coll Cardiol 2020;76:1609–1621. [DOI] [PubMed] [Google Scholar]

[ehab504-B27] 27. Alam M, Bandeali SJ, Kayani WT, Ahmad W, Shahzad SA, Jneid H, Birnbaum Y, Kleiman NS, Coselli JS, Ballantyne CM, Lakkis N, Virani SS.. Comparison by meta-analysis of mortality after isolated coronary artery bypass grafting in women versus men. Am J Cardiol 2013;112:309–317. [DOI] [PubMed] [Google Scholar]

[ehab504-B28] 28. Gaudino M, Di Franco A, Rahouma M, Tam DY, Iannaccone M, Deb S, D'Ascenzo F, Abouarab AA, Girardi LN, Taggart DP, Fremes SE.. Unmeasured confounders in observational studies comparing bilateral versus single internal thoracic artery for coronary artery bypass grafting: a meta-analysis. J Am Heart Assoc 2018;7:e008010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ehab504-B29] 29. Kirmani BH, Holmes MV, Muir AD.. Long-term survival and freedom from reintervention after off-pump coronary artery bypass grafting: a propensity-matched study. Circulation 2016;134:1209–1220. [DOI] [PubMed] [Google Scholar]

[ehab504-B30] 30. Schwann TA, Engoren M, Bonnell M, Clancy C, Habib RH.. Comparison of late coronary artery bypass graft survival effects of radial artery versus saphenous vein grafting in male and female patients. Ann Thorac Surg 2012;94:1485–1491. [DOI] [PubMed] [Google Scholar]

[ehab504-B31] 31. Dimitrova KR, Hoffman DM, Geller CM, Ko W, Lucido DJ, Dincheva GR, Tranbaugh RF.. Radial artery grafting in women improves 15-year survival. J Thorac Cardiovasc Surg 2013;146:1467–1473. [DOI] [PubMed] [Google Scholar]

[ehab504-B32] 32. Kurlansky PA, Traad EA, Dorman MJ, Galbut DL, Zucker M, Ebra G.. Bilateral internal mammary artery grafting reverses the negative influence of gender on outcomes of coronary artery bypass grafting surgery. Eur J Cardiothorac Surg 2013;44:54–63. [DOI] [PubMed] [Google Scholar]

[ehab504-B33] 33. Vrancic JM, Navia DO, Espinoza JC, Piccinini F, Camporrotondo M, Benzadon M, Dorsa A.. Is sex a risk factor for death in patients with bilateral internal thoracic artery grafts? J Thorac Cardiovasc Surg 2019;158:1345–1353.e1. [DOI] [PubMed] [Google Scholar]

[ehab504-B34] 34. Kurlansky PA, Traad EA, Galbut DL, Zucker M, Ebra G.. Efficacy of single versus bilateral internal mammary artery grafting in women: a long-term study. Ann Thorac Surg 2001;71:1949–1957; discussion 1957–1958. [DOI] [PubMed] [Google Scholar]

[ehab504-B35] 35. Benedetto U, Amrani M, Raja SG; Harefield Cardiac Outcomes Research Group. Guidance for the use of bilateral internal thoracic arteries according to survival benefit across age groups. J Thorac Cardiovasc Surg 2014;148:2706–2711. [DOI] [PubMed] [Google Scholar]

PERMALINK

Sex differences in outcomes after coronary artery bypass grafting: a pooled analysis of individual patient data

Mario Gaudino

Antonino Di Franco

John H Alexander

Faisal Bakaeen

Natalia Egorova

Paul Kurlansky

Andreas Boening

Joanna Chikwe

Michelle Demetres

Philip J Devereaux

Anno Diegeler

Arnaldo Dimagli

Marcus Flather

Irbaz Hameed

Andre Lamy

Jennifer S Lawton

Wilko Reents

N Bryce Robinson

Katia Audisio

Mohamed Rahouma

Patrick W Serruys

Hironori Hara

David P Taggart

Leonard N Girardi

Stephen E Fremes

Umberto Benedetto

Abstract

Aims

Methods and results

Conclusions

Graphical Abstract

Introduction

Methods

Study protocol

Selection of the trials

Data collection and merging

Outcomes

Statistical analysis

Primary analysis

Secondary analysis

Supplementary analysis with focus on preoperative left ventricular ejection fraction

Supplementary analysis based on the Open Heart Surgery Registry

Supplementary analysis including trial-level data of percutaneous intervention vs. coronary artery bypass grafting

Results

Trials description

Table 1.

Primary analysis

Table 2.

Table 3.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Secondary analysis

Supplementary analyses

Discussion

Supplementary material

Funding

Ethical approval

Data availability

Supplementary Material

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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