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Long-term outcome in men and women after CABG; results from the IMAGINE trial

  • Author Footnotes
    1 shared first author.
    Hester M. den Ruijter
    Footnotes
    1 shared first author.
    Affiliations
    Experimental Cardiology Laboratory, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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  • Author Footnotes
    1 shared first author.
    Saskia Haitjema
    Correspondence
    Corresponding author. Experimental Cardiology, University Medical Center Utrecht, Room G02.523, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.
    Footnotes
    1 shared first author.
    Affiliations
    Experimental Cardiology Laboratory, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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  • Manon G. van der Meer
    Affiliations
    Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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  • Pim van der Harst
    Affiliations
    Experimental Cardiology Laboratory, University Medical Center Groningen, Groningen, The Netherlands

    Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands-Netherlands Heart Institute, Utrecht, The Netherlands
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  • Jean L. Rouleau
    Affiliations
    Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, University of Montreal, Montreal, Canada
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  • Folkert W. Asselbergs
    Affiliations
    Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands

    Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom

    Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands-Netherlands Heart Institute, Utrecht, The Netherlands
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  • Wiek H. van Gilst
    Affiliations
    Experimental Cardiology Laboratory, University Medical Center Groningen, Groningen, The Netherlands
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  • IMAGINE Investigators
  • Author Footnotes
    1 shared first author.
Open AccessPublished:February 23, 2015DOI:https://doi.org/10.1016/j.atherosclerosis.2015.02.039

      Highlights

      • We researched sex-differences in long-term outcome after CABG.
      • Women have a worse long-term outcome after CABG than men in univariate analysis.
      • Adjusting for confounders in this small sample made sex a non-significant predictor.
      • Definite answers should come from studies comprising a larger number of women.

      Abstract

      Background

      The aim of this study is to determine sex differences in long-term outcome after coronary artery bypass grafting (CABG).

      Methods

      The international randomized controlled IMAGINE study included 2553 consecutive patients with a left ventricular ejection fraction of >40% who underwent isolated CABG. Median follow-up was 32 months (IQR 17–42 months). The composite endpoint comprised of death, myocardial infarction (MI), cerebrovascular event, angina, revascularization and congestive heart failure. Cox regression analysis was used to examine sex differences in outcome post-CABG.

      Results

      Of the 2553 patients, 2229 were men and 324 (13%) were women. Women were older and more often reported diabetes and hypertension. Smoking and impaired renal function were more prevalent in men. Women experienced a higher event rate during follow-up (composite endpoint 18% vs 12%; P = 0.007). Cox regression showed an increased risk of the composite endpoint in women after adjustment for age (HR 1.48 (95% CI: 1.11–1.97)) which was non-significant after additional adjustment for other confounders (HR 1.26 (95% CI: 0.92–1.72)).

      Conclusion

      Women have a worse long-term outcome after CABG than men in univariate analysis. However, after adjusting for potential confounders female sex became a non-significant predictor for prognosis, possibly due to the small sample size of women. Definite answers regarding sex-differences in long-term outcome after CABG should come from future pooling of studies comprising a larger number of women.

      Keywords

      1. Introduction

      Coronary artery disease (CAD) is the main cause of death in women older than 65 years [
      • Group Members
      • Roger V.L.
      • Go A.S.
      • Lloyd-Jones D.M.
      • Benjamin E.J.
      • Berry J.D.
      • Borden W.B.
      • Bravata D.M.
      • Dai S.
      • Ford E.S.
      • Fox C.S.
      • Fullerton H.J.
      • Gillespie C.
      • Hailpern S.M.
      • Heit J.A.
      • Howard V.J.
      • Kissela B.M.
      • Kittner S.J.
      • Lackland D.T.
      • Lichtman J.H.
      • Lisabeth L.D.
      • Makuc D.M.
      • Marcus G.M.
      • Marelli A.
      • Matchar D.B.
      • Moy C.S.
      • Mozaffarian D.
      • Mussolino M.E.
      • Nichol G.
      • Paynter N.P.
      • Soliman E.Z.
      • Sorlie P.D.
      • Sotoodehnia N.
      • Turan T.N.
      • Virani S.S.
      • Wong N.D.
      • Woo D.
      • Turner M.B.
      on behalf of the American Heart Association Statistics Committee and Stroke Statistics SubcommitteeOn behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke Statistics–2012 update: a report from the American Heart Association.
      ]. In 2008 the prevalence of cardiovascular disease in the United States was 35.0% in women compared to 37.4% in men. However age-adjusted mortality rates were higher in women, namely 51.7% versus 48.3% [
      • Group Members
      • Roger V.L.
      • Go A.S.
      • Lloyd-Jones D.M.
      • Benjamin E.J.
      • Berry J.D.
      • Borden W.B.
      • Bravata D.M.
      • Dai S.
      • Ford E.S.
      • Fox C.S.
      • Fullerton H.J.
      • Gillespie C.
      • Hailpern S.M.
      • Heit J.A.
      • Howard V.J.
      • Kissela B.M.
      • Kittner S.J.
      • Lackland D.T.
      • Lichtman J.H.
      • Lisabeth L.D.
      • Makuc D.M.
      • Marcus G.M.
      • Marelli A.
      • Matchar D.B.
      • Moy C.S.
      • Mozaffarian D.
      • Mussolino M.E.
      • Nichol G.
      • Paynter N.P.
      • Soliman E.Z.
      • Sorlie P.D.
      • Sotoodehnia N.
      • Turan T.N.
      • Virani S.S.
      • Wong N.D.
      • Woo D.
      • Turner M.B.
      on behalf of the American Heart Association Statistics Committee and Stroke Statistics SubcommitteeOn behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke Statistics–2012 update: a report from the American Heart Association.
      ]. Previous studies suggest sex differences in treatment and prognosis of CAD, but many discrepancies exist between different studies [
      • Alam M.
      • Lee V.V.
      • Elayda M.A.
      • Shahzad S.A.
      • Yang E.Y.
      • Nambi V.
      • Jneid H.
      • Pan W.
      • Coulter S.
      • Wilson J.M.
      • Ramanathan K.B.
      • Ballantyne C.M.
      • Virani S.S.
      Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.
      ,
      • Cartier R.
      • Bouchot O.
      • El-Hamamsy I.
      Influence of sex and age on long-term survival in systematic off-pump coronary artery bypass surgery.
      ,
      • Ennker I.C.
      • Albert A.
      • Pietrowski D.
      • Bauer K.
      • Ennker J.
      • Florath I.
      Impact of gender on outcome after coronary artery bypass surgery.
      ,
      • Fu S.P.
      • Zheng Z.
      • Yuan X.
      • Zhang S.J.
      • Gao H.W.
      • Li Y.
      • Hu S.S.
      Impact of off-pump techniques on sex differences in early and late outcomes after isolated coronary artery bypass grafts.
      ,
      • Puskas J.D.
      • Edwards F.H.
      • Pappas P.A.
      • O'Brien S.
      • Peterson E.D.
      • Kilgo P.
      • Ferguson Jr., T.B.
      Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Kutner M.
      • Pusca S.V.
      • Lattouf O.
      • Guyton R.A.
      Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Lattouf O.M.
      • Thourani V.H.
      • Cooper W.A.
      • Vassiliades T.A.
      • Chen E.P.
      • Vega J.D.
      • Guyton R.A.
      Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.
      ,
      • Basaran M.
      • Selimoglu O.
      • Ozcan H.
      • Ogus H.
      • Kafali E.
      • Ozcelebi C.
      • Ogus T.N.
      Being an elderly woman: is it a risk factor for morbidity after coronary artery bypass surgery?.
      ,
      • Bukkapatnam R.N.
      • Yeo K.K.
      • Li Z.
      • Amsterdam E.A.
      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      ,
      • Czech B.
      • Kucewicz-Czech E.
      • Pacholewicz J.
      • Wojarski J.
      • Puzio J.
      • Przybylski R.
      • Farmas A.
      • Ryfinski B.
      • Zembala M.
      Early results of coronary artery bypass graft surgery in women.
      ,
      • Fukui T.
      • Takanashi S.
      Gender differences in clinical and angiographic outcomes after coronary artery bypass surgery.
      ,
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ,
      • Uva M.S.
      • Freitas S.
      • Pedro A.
      • Matias F.
      • Mesquita A.
      • Bau J.
      • Pinho J.
      • Fernandes J.
      • Magalhaes M.P.
      Off-pump coronary artery bypass surgery in women.
      ,
      • Eifert S.
      • Kilian E.
      • Beiras-Fernandez A.
      • Juchem G.
      • Reichart B.
      • Lamm P.
      Early and mid term mortality after coronary artery bypass grafting in women depends on the surgical protocol: retrospective analysis of 3441 on- and off-pump coronary artery bypass grafting procedures.
      ]. It remains uncertain whether these differences in outcome are due to a different risk burden between men and women or whether female sex is an independent risk factor of worse outcome and prognosis. Age is a major confounder, as younger, but not older, women have a higher mortality rate than men after myocardial infarction with or without intervention [
      • Vaccarino V.
      • Abramson J.L.
      • Veledar E.
      • Weintraub W.S.
      Sex differences in hospital mortality after coronary artery bypass surgery: evidence for a higher mortality in younger women.
      ,
      • Vaccarino V.
      • Krumholz H.M.
      • Yarzebski J.
      • Gore J.M.
      • Goldberg R.J.
      Sex differences in 2-year mortality after hospital discharge for myocardial infarction.
      ,
      • Radovanovic D.
      • Erne P.
      • Urban P.
      • Bertel O.
      • Rickli H.
      • Gaspoz J.M.
      AMIS Plus Investigators
      Gender differences in management and outcomes in patients with acute coronary syndromes: results on 20,290 patients from the AMIS Plus Registry.
      ]. Furthermore, women undergo coronary angiography or percutaneous coronary intervention less often as compared to men [
      • Radovanovic D.
      • Erne P.
      • Urban P.
      • Bertel O.
      • Rickli H.
      • Gaspoz J.M.
      AMIS Plus Investigators
      Gender differences in management and outcomes in patients with acute coronary syndromes: results on 20,290 patients from the AMIS Plus Registry.
      ,
      • Matsui K.
      • Fukui T.
      • Hira K.
      • Sobashima A.
      • Okamatsu S.
      • Hayashida N.
      • Tanaka S.
      • Nobuyoshi M.
      Impact of sex and its interaction with age on the management of and outcome for patients with acute myocardial infarction in 4 Japanese hospitals.
      ,
      • Reynolds H.R.
      • Farkouh M.E.
      • Lincoff A.M.
      • Hsu A.
      • Swahn E.
      • Sadowski Z.P.
      • White J.A.
      • Topol E.J.
      • Hochman J.S.
      GUSTO V Investigators
      Impact of female sex on death and bleeding after fibrinolytic treatment of myocardial infarction in GUSTO V.
      ]. The influence of female sex on the outcome after coronary artery bypass grafting (CABG) remains unclear, as previous studies are contradictory [
      • Alam M.
      • Lee V.V.
      • Elayda M.A.
      • Shahzad S.A.
      • Yang E.Y.
      • Nambi V.
      • Jneid H.
      • Pan W.
      • Coulter S.
      • Wilson J.M.
      • Ramanathan K.B.
      • Ballantyne C.M.
      • Virani S.S.
      Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.
      ,
      • Cartier R.
      • Bouchot O.
      • El-Hamamsy I.
      Influence of sex and age on long-term survival in systematic off-pump coronary artery bypass surgery.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Lattouf O.M.
      • Thourani V.H.
      • Cooper W.A.
      • Vassiliades T.A.
      • Chen E.P.
      • Vega J.D.
      • Guyton R.A.
      Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.
      ,
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ]. In order to determine possible sex differences in long-term outcome after CABG, data from the Ischemia Management with Accupril post-bypass Graft via inhibition of the coNverting Enzyme (IMAGINE) were analysed. IMAGINE is a multicentre, international randomized controlled trial with extensive data concerning baseline characteristics and operational techniques.

      2. Methods

      2.1 Patient characteristics

      The design and the main results of the Ischemia Management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial have been previously described in detail [
      • Rouleau J.L.
      • Warnica W.J.
      • Baillot R.
      • Block P.J.
      • Chocron S.
      • Johnstone D.
      • Myers M.G.
      • Calciu C.D.
      • Dalle-Ave S.
      • Martineau P.
      • Mormont C.
      • van Gilst W.H.
      IMAGINE (Ischemia Management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme) Investigators
      Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery.
      ,
      • Warnica J.W.
      • Gilst W.V.
      • Baillot R.
      • Johnstone D.
      • Block P.
      • Myers M.G.
      • Chocron S.
      • Ave S.D.
      • Martineau P.
      • Rouleau J.L.
      Ischemia Management with Accupril post bypass Graft via Inhibition of angiotensin coNverting enzyme (IMAGINE): a multicentre randomized trial – design and rationale.
      ]. In brief, the IMAGINE trial is an international, randomized, double-blind, placebo-controlled, multicentre study that investigated whether early administration of an angiotensin-converting enzyme (ACE) inhibitor after CABG reduced cardiovascular events compared to placebo in stable patients. Patients older than 18 years with a left ventricular ejection fraction (LVEF) of ≥40% who were stable after CABG were included. Exclusion criteria consisted of intolerance or contraindication to ACE inhibitors, insulin-dependent diabetes, concomitant cardiac surgery, serious concomitant disease including severe renal impairment, significant perioperative myocardial infarction, pregnancy and investigational drug use <30 days. The 2553 patients included in this study between 1999 and 2004 were randomly assigned to quinapril 10–20 mg (n = 1280) or to placebo (n = 1273). On average patients were randomized 4 ± 2 days after CABG, with a maximum of 7 days (10 days in France). The primary endpoint was a composite of time to first occurrence of cardiovascular death or resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina, stroke and congestive heart failure that required hospitalization. Five patients were lost to follow-up (0.2%).
      For the current analyses all available follow up time was used. The ethics committees of all participating institutions approved the research protocol and all patients gave written informed consent.

      2.2 Statistical analysis

      Patients were stratified by sex. Baseline categorical variables are presented as percentages (numbers). Differences between sexes were calculated by Chi–Square test. Continuous variables are described as the mean value ± standard deviation (SD) if normally distributed or the median value if the distribution was skewed. Possible differences were tested by t-test. All statistical tests were two-sided using p < 0.05 as level of significance. The primary endpoint was evaluated using a Cox proportional hazard model where men served as the reference category. Results are expressed as hazard ratios (HR) with 95% confidence intervals (95% CI). To identify possible confounders all baseline characteristics and surgical characteristics were related to the composite endpoint separately, adjusted for age. Correlation with the determinant sex was evaluated by a Pearson's correlation chi-square in variables that were significantly associated with the composite endpoint. Those with a p-value <0.1 at Pearson's correlation chi-square, as well as age and sex, were added in the multivariate model. Since previous studies demonstrated that body surface area (BSA) is associated with a worse outcome post-CABG in female sex we used BSA instead of body mass index [
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ]. Because of the well-documented surgical characteristics, a subanalysis was made regarding the type of grafts used during CABG. All statistical analyses were performed using SPSS Version 21.0.

      3. Results

      3.1 Patient characteristics

      Out of the 2553 included patients 324 (13%) were women. Median follow-up was 32 months in both men and women (IQR 17–42 in men, IQR 15–42 in women). Baseline characteristics are shown in Table 1. Women were on average 5 years older than men and more often reported hypertension and a family history of CAD. Men more often smoked and revealed decreased renal function (all P < 0.01).
      Table 1Baseline characteristics.
      Men (n = 2229)Women (n = 324)P-value
      Age, years (SD)60 ± 1065 ± 10<0.01
      Median follow-up in months (IQR)32 (17–42)32 (15–42)0.21
      Medical history
       Myocardial infarction40 (887)35 (114)0.11
       CABG3 (58)2 (6)0.42
       Percutaneous coronary intervention17 (388)21 (67)0.15
       Peripheral vascular disease7 (151)9 (30)0.10
       Stroke/TIA1 (33)1 (4)0.73
      Cardiovascular risk factors
       LDL cholesterol (mmol/L) (SD)2.9 ± 12.9 ± 10.95
       Diabetes10 (212)13 (41)0.08
       HbA1c (mmol/mol) (SD)39 ± 841 ± 32<0.01
       Systolic blood pressure (mmHg) (SD)121 ± 14124 ± 150.11
       Current or former smoker74 (1658)52 (167)<0.01
       Family history of coronary artery disease67 (1480)73 (235)0.03
      Body surface area (m2) (SD)2.0 ± 0.21.8 ± 0.2<0.01
      Heart rate (bpm) (SD)82 ± 1381 ± 120.23
      Left ventricular ejection fraction (%) (SD)60 ± 761 ± 100.43
      MDRD (estimated GFR based on creatinine) (SD)63 ± 15108 ± 32<0.01
      Medication
       Acetylsalicylic acid (ASA)74 (1567)72 (205)0.44
       Betablockers78 (1657)79 (224)0.92
       Calcium-channel blockers767 (36)107 (38)0.67
       Diuretics9 (184)9 (25)0.97
       ACE inhibitors21 (433)19 (54)0.55
       Statins65 (1384)60 (172)0.09
      Continuous variables are presented as mean ± SD; categorical variables are presented as percentages (n)SD, standard deviation; IQR, inter quartile range; LDL, low-density lipoprotein; MDRD, modification of diet in renal disease; GFR, glomerular filtration rate.

      3.2 Characteristics of CABG

      On average men received more grafts (3.3 versus 3.0 in women; P < 0.01) (see Table 2). The percentage of off-pump CABG compared to CABG on cardiopulmonary bypass did not differ between men and women (18% versus 21%, P = 0.19). Furthermore, there was no difference in complete revascularization, defined as all vessels >1 mm with a stenosis >70% having been bypassed, between women and men (P = 0.21).
      Table 2Surgical characteristics.
      Patient characteristics % (n)Men (n = 2229)Women (n = 324)P-value
      Off-pump CABG18 (407)21 (69)0.19
      Number of grafts3.3 ± 1.13.0 ± 1.1<0.01
      Use of LIMA95 (2120)92 (297)0.01
      Use of RIMA19 (415)9 (28)<0.01
      Use of free IMA3 (61)6 (18)<0.01
      Use of other arterial grafts20 (445)10 (31)<0.01
      Use of saphenous vein79 (1757)79 (257)0.84
      Endarterectomy6 (111)8 (22)0.21
      Complete revascularization88 (1962)90 (293)0.21
      Continuous variables are presented as mean ± SD; categorical variables are presented as percentages (n).
      CABG, coronary artery bypass grafting; Free artery bypass, composite of radial artery, all other arteries than LIMA or RIMA; IMA, internal mammary artery; LIMA, left internal mammary artery; mixed grafts, arterial or venous grafts; RIMA, right internal mammary artery.

      3.3 Endpoint

      Women were more likely to experience the composite endpoint, 18% versus 12% in men (P < 0.01), as shown in Table 3. This difference is mainly driven by the distribution of unstable angina (5% in women vs 1.9% in men), coronary revascularization (1.2% in women vs 0.4% in men) and congestive heart failure (2.5% in women vs 0.9% in men).
      Table 3Composite endpoint.
      Patient characteristicsMen (n = 2229)Women (n = 324)P-value
      Composite endpoint12 (273)18 (57)<0.01
       Cardiovascular death0.8 (17)1.2 (4)
       Myocardial infarction (non-fatal)1 (22)1.2 (4)
       Documented angina (not req. hosp.)6.1 (137)6.2 (20)
       Unstable angina (req. hosp.)1.9 (43)5 (15)
       Coronary revascularization0.4 (9)1.2 (4)
       Stroke1.0 (23)0.3 (1)
       Resuscitation or cardiac arrest0.1 (2)0.3 (1)
       Congestive heart failure (req. hosp.)0.9 (20)2.5 (8)
      Categorical variables are presented as percentages (n).
      MDRD, estimated GFR based on creatinine; Req. hosp., requiring hospitalization; TIA, transient ischemic attack.
      Cox regression analysis demonstrated an increased risk of the composite endpoint in women compared to men after adjustment for age with an HR of 1.48 (95%CI 1.11–1.97). Seven other variables were after adjustment for age associated with the composite endpoint, family history of CAD (HR 1.36 (95%CI: 1.06–1.74)), a medical history of PCI (HR 1.65 (95%CI: 1.28–2.11)), CABG (HR 2.28 (95%CI: 1.39–3.72)) or peripheral vascular disease (HR 1.80 (95%CI: 1.30–2.51)), BSA (HR 0.61 (95%CI: 0.38–0.98)), complete revascularization (HR 0.63 (95%CI: 0.48–0.85)) and number of grafts used (HR 0.78 (95%CI 0.71–0.87)). Of these seven variables only a family history of CAD (P = 0.03), number of grafts (P < 0.01) and BSA (P < 0.01) correlated with sex and were added to the multivariate model (Fig. 1). Female sex was not associated with the composite endpoint in the multivariate analysis (HR 1.26 (95%CI: 0.92–1.72), Fig. 1) nor was BSA (HR 0.74 (95%CI: 0.45–1.23). A family history of CAD remained associated with the composite endpoint (HR 1.35 (95%CI: 1.05–1.73)) as well as number of grafts used (HR 0.79 (95%CI: 0.72–0.88)).
      Figure thumbnail gr1
      Fig. 1Cox survival plot. Cox survival plot for composite endpoints in women and men.
      In the original IMAGINE trial, there were no differences in the incidence of the primary endpoint between the quinapril and placebo group after subdividing by sex.

      4. Discussion

      The current study demonstrates that women have an increased risk of an adverse outcome after CABG compared to men during 2.5 years of follow-up. However, in the multivariate analysis female sex is not an independent predictor for developing the composite endpoint in this cohort potentially due to lack of power. At baseline women were older and more often had hypertension, a family history of CAD and a smaller BSA. On the other hand men smoked more often and had more frequently renal dysfunction. In regard to other studies both men and women included in the IMAGINE trial reported a relatively low burden of cardiovascular risk factors. Interestingly, our results showed no differences in percentage of off-pump CABG between men and women and no benefit of off-pump CABG for the composite endpoint in both men and women. Previous studies showed an increased risk of adverse outcome in women for CABG on cardiopulmonary bypass, compared to off-pump CABG [
      • Ennker I.C.
      • Albert A.
      • Pietrowski D.
      • Bauer K.
      • Ennker J.
      • Florath I.
      Impact of gender on outcome after coronary artery bypass surgery.
      ,
      • Fu S.P.
      • Zheng Z.
      • Yuan X.
      • Zhang S.J.
      • Gao H.W.
      • Li Y.
      • Hu S.S.
      Impact of off-pump techniques on sex differences in early and late outcomes after isolated coronary artery bypass grafts.
      ,
      • Puskas J.D.
      • Edwards F.H.
      • Pappas P.A.
      • O'Brien S.
      • Peterson E.D.
      • Kilgo P.
      • Ferguson Jr., T.B.
      Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Kutner M.
      • Pusca S.V.
      • Lattouf O.
      • Guyton R.A.
      Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Lattouf O.M.
      • Thourani V.H.
      • Cooper W.A.
      • Vassiliades T.A.
      • Chen E.P.
      • Vega J.D.
      • Guyton R.A.
      Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.
      ,
      • Bukkapatnam R.N.
      • Yeo K.K.
      • Li Z.
      • Amsterdam E.A.
      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ]. The majority of prior studies included emergency CABGs whereas we excluded these unstable patients, which makes it difficult to directly compare results [
      • Ennker I.C.
      • Albert A.
      • Pietrowski D.
      • Bauer K.
      • Ennker J.
      • Florath I.
      Impact of gender on outcome after coronary artery bypass surgery.
      ,
      • Fu S.P.
      • Zheng Z.
      • Yuan X.
      • Zhang S.J.
      • Gao H.W.
      • Li Y.
      • Hu S.S.
      Impact of off-pump techniques on sex differences in early and late outcomes after isolated coronary artery bypass grafts.
      ,
      • Puskas J.D.
      • Edwards F.H.
      • Pappas P.A.
      • O'Brien S.
      • Peterson E.D.
      • Kilgo P.
      • Ferguson Jr., T.B.
      Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Kutner M.
      • Pusca S.V.
      • Lattouf O.
      • Guyton R.A.
      Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Lattouf O.M.
      • Thourani V.H.
      • Cooper W.A.
      • Vassiliades T.A.
      • Chen E.P.
      • Vega J.D.
      • Guyton R.A.
      Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.
      ,
      • Bukkapatnam R.N.
      • Yeo K.K.
      • Li Z.
      • Amsterdam E.A.
      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      ,
      • Czech B.
      • Kucewicz-Czech E.
      • Pacholewicz J.
      • Wojarski J.
      • Puzio J.
      • Przybylski R.
      • Farmas A.
      • Ryfinski B.
      • Zembala M.
      Early results of coronary artery bypass graft surgery in women.
      ,
      • Fukui T.
      • Takanashi S.
      Gender differences in clinical and angiographic outcomes after coronary artery bypass surgery.
      ,
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ,
      • Uva M.S.
      • Freitas S.
      • Pedro A.
      • Matias F.
      • Mesquita A.
      • Bau J.
      • Pinho J.
      • Fernandes J.
      • Magalhaes M.P.
      Off-pump coronary artery bypass surgery in women.
      ]. Furthermore, we used a composite endpoint where others used death as primary outcome. Some studies showed an increased risk in women for early mortality [
      • Alam M.
      • Lee V.V.
      • Elayda M.A.
      • Shahzad S.A.
      • Yang E.Y.
      • Nambi V.
      • Jneid H.
      • Pan W.
      • Coulter S.
      • Wilson J.M.
      • Ramanathan K.B.
      • Ballantyne C.M.
      • Virani S.S.
      Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Lattouf O.M.
      • Thourani V.H.
      • Cooper W.A.
      • Vassiliades T.A.
      • Chen E.P.
      • Vega J.D.
      • Guyton R.A.
      Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.
      ,
      • Bukkapatnam R.N.
      • Yeo K.K.
      • Li Z.
      • Amsterdam E.A.
      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      ], but the majority found no sex differences [
      • Cartier R.
      • Bouchot O.
      • El-Hamamsy I.
      Influence of sex and age on long-term survival in systematic off-pump coronary artery bypass surgery.
      ,
      • Ennker I.C.
      • Albert A.
      • Pietrowski D.
      • Bauer K.
      • Ennker J.
      • Florath I.
      Impact of gender on outcome after coronary artery bypass surgery.
      ,
      • Fukui T.
      • Takanashi S.
      Gender differences in clinical and angiographic outcomes after coronary artery bypass surgery.
      ,
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ,
      • Uva M.S.
      • Freitas S.
      • Pedro A.
      • Matias F.
      • Mesquita A.
      • Bau J.
      • Pinho J.
      • Fernandes J.
      • Magalhaes M.P.
      Off-pump coronary artery bypass surgery in women.
      ]. Others only found an increased risk for mortality in women after CABG on cardiopulmonary bypass and not after off-pump CABG [
      • Fu S.P.
      • Zheng Z.
      • Yuan X.
      • Zhang S.J.
      • Gao H.W.
      • Li Y.
      • Hu S.S.
      Impact of off-pump techniques on sex differences in early and late outcomes after isolated coronary artery bypass grafts.
      ,
      • Puskas J.D.
      • Edwards F.H.
      • Pappas P.A.
      • O'Brien S.
      • Peterson E.D.
      • Kilgo P.
      • Ferguson Jr., T.B.
      Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Kutner M.
      • Pusca S.V.
      • Lattouf O.
      • Guyton R.A.
      Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery.
      ,
      • Czech B.
      • Kucewicz-Czech E.
      • Pacholewicz J.
      • Wojarski J.
      • Puzio J.
      • Przybylski R.
      • Farmas A.
      • Ryfinski B.
      • Zembala M.
      Early results of coronary artery bypass graft surgery in women.
      ,
      • Eifert S.
      • Kilian E.
      • Beiras-Fernandez A.
      • Juchem G.
      • Reichart B.
      • Lamm P.
      Early and mid term mortality after coronary artery bypass grafting in women depends on the surgical protocol: retrospective analysis of 3441 on- and off-pump coronary artery bypass grafting procedures.
      ]. The higher risk in women we found in the univariate analysis is caused primarily by a higher rate of unstable angina and coronary revascularization as the number of deaths was equal in both sexes. This is consistent with the finding in this study that the number of grafts used is significant between women and men in the multivariate analysis. The difference in univariate analysis between women and men could therefore point towards a difference in coronary artery diameter: as women are smaller, they have smaller coronary arteries that are technically more demanding in CABG. Indeed, BSA was a confounding factor in this study.

      5. Limitations

      Main limitation of this study is the small sample size of women. Women comprised only 13% of our study population compared to 24% on average in other studies [
      • Alam M.
      • Lee V.V.
      • Elayda M.A.
      • Shahzad S.A.
      • Yang E.Y.
      • Nambi V.
      • Jneid H.
      • Pan W.
      • Coulter S.
      • Wilson J.M.
      • Ramanathan K.B.
      • Ballantyne C.M.
      • Virani S.S.
      Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.
      ,
      • Cartier R.
      • Bouchot O.
      • El-Hamamsy I.
      Influence of sex and age on long-term survival in systematic off-pump coronary artery bypass surgery.
      ,
      • Ennker I.C.
      • Albert A.
      • Pietrowski D.
      • Bauer K.
      • Ennker J.
      • Florath I.
      Impact of gender on outcome after coronary artery bypass surgery.
      ,
      • Fu S.P.
      • Zheng Z.
      • Yuan X.
      • Zhang S.J.
      • Gao H.W.
      • Li Y.
      • Hu S.S.
      Impact of off-pump techniques on sex differences in early and late outcomes after isolated coronary artery bypass grafts.
      ,
      • Puskas J.D.
      • Edwards F.H.
      • Pappas P.A.
      • O'Brien S.
      • Peterson E.D.
      • Kilgo P.
      • Ferguson Jr., T.B.
      Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Kutner M.
      • Pusca S.V.
      • Lattouf O.
      • Guyton R.A.
      Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Lattouf O.M.
      • Thourani V.H.
      • Cooper W.A.
      • Vassiliades T.A.
      • Chen E.P.
      • Vega J.D.
      • Guyton R.A.
      Off-pump coronary bypass provides reduced mortality and morbidity and equivalent 10-year survival.
      ,
      • Bukkapatnam R.N.
      • Yeo K.K.
      • Li Z.
      • Amsterdam E.A.
      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      ,
      • Czech B.
      • Kucewicz-Czech E.
      • Pacholewicz J.
      • Wojarski J.
      • Puzio J.
      • Przybylski R.
      • Farmas A.
      • Ryfinski B.
      • Zembala M.
      Early results of coronary artery bypass graft surgery in women.
      ,
      • Fukui T.
      • Takanashi S.
      Gender differences in clinical and angiographic outcomes after coronary artery bypass surgery.
      ,
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ,
      • Uva M.S.
      • Freitas S.
      • Pedro A.
      • Matias F.
      • Mesquita A.
      • Bau J.
      • Pinho J.
      • Fernandes J.
      • Magalhaes M.P.
      Off-pump coronary artery bypass surgery in women.
      ,
      • Eifert S.
      • Kilian E.
      • Beiras-Fernandez A.
      • Juchem G.
      • Reichart B.
      • Lamm P.
      Early and mid term mortality after coronary artery bypass grafting in women depends on the surgical protocol: retrospective analysis of 3441 on- and off-pump coronary artery bypass grafting procedures.
      ]. Unfortunately no screenings log, with numbers screened patients and the reason of exclusion, is available so the low inclusion rate in women remains elusive. One of the possible explanations is the exclusion of patients with severe comorbidities, as women are known to be more severely impaired. The sample size of women introduces an unexpected power problem in the multivariate model, where sex does not seem to associate with the composite endpoint whereas the cox survival plot shows a difference between women and men.
      Our results are only applicable to stable patients undergoing CABG since unstable patients were excluded from the study, just as patients with a clinical need for ACE-inhibitors (e.g. severe renal insufficiency and insulin dependent diabetes). We are to our knowledge the first study to include only stable patients and since a large part of the CABG population is stable before surgery, it is relevant to investigate sex differences in outcome in this subpopulation. It could be that sex differences are still present in the unstable group.
      Echocardiography testing for diastolic dysfunction which may eventually evolve in to heart failure with preserved ejection fraction (HFpEF) was not performed. As diastolic dysfunction is common in the general population [
      • Kuznetsova T.
      • Herbots L.
      • López B.
      • Jin Y.
      • Richart T.
      • Thijs L.
      • González A.
      • Herregods M.C.
      • Fagard R.H.
      • Díez J.
      • Staessen J.A.
      Prevalence of left ventricular diastolic dysfunction in a general population.
      ] more prevalent among women undergoing cardiac surgery [
      • Ferreira R.G.
      • Worthington A.
      • Huang C.C.
      • Aranki S.F.
      • Muehlschlegel J.D.
      Sex differences in the prevalence of diastolic dysfunction in cardiac surgical patients.
      ] and associated with worse outcome in CAD patients [
      • Ren X.
      • Ristow B.
      • Na B.
      • Ali S.
      • Schiller N.B.
      • Whooley M.A.
      Prevalence and prognosis of asymptomatic left ventricular diastolic dysfunction in ambulatory patients with coronary heart disease.
      ], this could be a confounding factor. Also, no data were available on relief of angina symptoms, one of the indications for CABG surgery. However, we do not think this affected the results, since persisting angina was well-documented.
      The difference between women and men found in this study was mainly due to differences in ‘soft’ endpoints such as unstable angina and cardiac revascularization, rather than more robust endpoints such as death. As these ‘soft’ endpoints are more prone to misclassification, this could potentially have induced non-differential (more in women) misclassification of the outcome. Unfortunately, this type of bias is difficult to overcome and may have overestimated the sex difference.
      The duration of follow-up was limited to 2.5 years. Although the majority of the present studies had a limited follow-up of 30 days after CABG [
      • Alam M.
      • Lee V.V.
      • Elayda M.A.
      • Shahzad S.A.
      • Yang E.Y.
      • Nambi V.
      • Jneid H.
      • Pan W.
      • Coulter S.
      • Wilson J.M.
      • Ramanathan K.B.
      • Ballantyne C.M.
      • Virani S.S.
      Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.
      ,
      • Ennker I.C.
      • Albert A.
      • Pietrowski D.
      • Bauer K.
      • Ennker J.
      • Florath I.
      Impact of gender on outcome after coronary artery bypass surgery.
      ,
      • Puskas J.D.
      • Edwards F.H.
      • Pappas P.A.
      • O'Brien S.
      • Peterson E.D.
      • Kilgo P.
      • Ferguson Jr., T.B.
      Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting.
      ,
      • Puskas J.D.
      • Kilgo P.D.
      • Kutner M.
      • Pusca S.V.
      • Lattouf O.
      • Guyton R.A.
      Off-pump techniques disproportionately benefit women and narrow the gender disparity in outcomes after coronary artery bypass surgery.
      ,
      • Bukkapatnam R.N.
      • Yeo K.K.
      • Li Z.
      • Amsterdam E.A.
      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      ,
      • Czech B.
      • Kucewicz-Czech E.
      • Pacholewicz J.
      • Wojarski J.
      • Puzio J.
      • Przybylski R.
      • Farmas A.
      • Ryfinski B.
      • Zembala M.
      Early results of coronary artery bypass graft surgery in women.
      ,
      • Fukui T.
      • Takanashi S.
      Gender differences in clinical and angiographic outcomes after coronary artery bypass surgery.
      ,
      • Humphries K.H.
      • Gao M.
      • Pu A.
      • Lichtenstein S.
      • Thompson C.R.
      Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004).
      ,
      • Ried M.
      • Lunz D.
      • Kobuch R.
      • Rupprecht L.
      • Keyser A.
      • Hilker M.
      • Schmid C.
      • Diez C.
      Gender's impact on outcome in coronary surgery with minimized extracorporeal circulation.
      ,
      • Uva M.S.
      • Freitas S.
      • Pedro A.
      • Matias F.
      • Mesquita A.
      • Bau J.
      • Pinho J.
      • Fernandes J.
      • Magalhaes M.P.
      Off-pump coronary artery bypass surgery in women.
      ], some have shown a decrease in the sex gap after long-term follow-up [
      • Cartier R.
      • Bouchot O.
      • El-Hamamsy I.
      Influence of sex and age on long-term survival in systematic off-pump coronary artery bypass surgery.
      ,
      • Koch C.G.
      • Weng Y.S.
      • Zhou S.X.
      • Savino J.S.
      • Mathew J.P.
      • Hsu P.H.
      • Saidman L.J.
      • Mangano D.T.
      Ischemia Research and Education FoundationMulticenter Study of Perioperative Ischemia Research Group
      Prevalence of risk factors, and not gender per se, determines short- and long-term survival after coronary artery bypass surgery.
      ], as described earlier by M Claassen et al. [
      • Claassen M.
      • Sybrandy K.C.
      • Appelman Y.E.
      • Asselbergs F.W.
      Gender gap in acute coronary heart disease: myth or reality?.
      ]. Future studies should examine a larger number of women during long-term follow-up. For example, an individual participant data analysis of current studies could improve the power to detect sex-specific differences and their determinants in outcome between women and men after CABG.

      6. Conclusion

      Women have a worse long-term outcome after CABG than men in univariate analysis. However, after adjusting for potential confounders female sex became a non-significant predictor for prognosis, possibly due to the small sample size of women. Definite answers regarding sex-differences in long-term outcome after CABG should come from future pooling of studies comprising a larger number of women.

      Conflict of interests

      None.

      Sources of funding

      S. Haitjema is funded through the Queen of Hearts grant of the Dutch Heart Foundation (2013T084) and the FP7 EU project [email protected] (HEALTH-F2-2013-601456). Folkert W. Asselbergs is supported by the UCL Hospitals NIHR Biomedical Research Centre and a Dekker scholarship-Junior Staff Member 2014T001 – Dutch Heart Foundation. The original IMAGINE study was supported by Pfizer Canada, the Netherlands, Belgium and France.

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      Linked Article

      • Importance of sex and gender in atherosclerosis and cardiovascular disease
        AtherosclerosisVol. 241Issue 1
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          In this special issue of the journal, there are papers on bone health and coronary artery calcification, age and sex differences in the effect of parental stroke on the progression of carotid intima-media thickness, macrophage subsets in the adipose tissue by sex and by reproductive age of women, uric acid levels and metabolic syndrome, sex differences in cardiovascular risk factors and disease prevention, severity of stable coronary artery disease and its biomarkers, cardiovascular disease and autoimmune diseases genetics of cardiovascular disease, outcome after CABG; association of serum phosphorus with subclinical atherosclerosis in chronic kidney disease and relationship of uric acid levels to coronary disease.
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      • Sex matters to the heart: A special issue dedicated to the impact of sex related differences of cardiovascular diseases
        AtherosclerosisVol. 241Issue 1
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          Ever since the early 1980s most cardiovascular research has focused on men [1]. This phenomenon has led to the under appreciation of sex-differences in cardiovascular disease (CVD) from an etiological, prognostic, diagnostic and therapeutic perspective. Several initiatives to promote women's health, such as the Women's Health Initiative [2] have been initiated and have changed the practice of cardiovascular disease prevention in women over the past decade. This ultimately led to the first guidelines for cardiovascular disease prevention in women by the American Heart Association in 1999 [3].
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