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Coronary Artery Bypass Grafting Following Acute Coronary Syndrome: Impact of Gender

  • Eilon Ram
    Correspondence
    Address reprint requests to Eilon Ram MD, Department of Cardiac Surgery, Sheba Medical Center, Tel Hashomer, Israel 52621.
    Affiliations
    Department of Cardiac Surgery and Cardiology, Tel Aviv University, Israel

    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel
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  • Leonid Sternik
    Affiliations
    Department of Cardiac Surgery and Cardiology, Tel Aviv University, Israel

    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel
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  • Yaron Moshkovitz
    Affiliations
    Department of Cardiothoracic Surgery, Assuta Medical Center, Tel Aviv, Israel
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  • Zaza Iakobishvili
    Affiliations
    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel

    Clalit Health Services, Tel-Aviv, Israel

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Elchanan Zuroff
    Affiliations
    Department of Cardiac Surgery and Cardiology, Tel Aviv University, Israel

    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel
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  • Yael Peled
    Affiliations
    Department of Cardiac Surgery and Cardiology, Tel Aviv University, Israel

    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel
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  • Romana Herscovici
    Affiliations
    Department of Cardiac Surgery and Cardiology, Tel Aviv University, Israel

    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel
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  • Ehud Raanani
    Affiliations
    Department of Cardiac Surgery and Cardiology, Tel Aviv University, Israel

    Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Israel
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      The impact of gender on clinical outcomes after coronary artery bypass grafting (CABG) has generated conflicting results. We investigated the impact of gender, on 30 day mortality, complications and late survival in patients with acute coronary syndrome (ACS) undergoing CABG. The study included 1308 patients enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for ACS and underwent CABG. Of them, 1045 (80%) were men and 263 (20%) women. While women were older and had more hypertension and hyperlipidemia, they demonstrated less diabetes mellitus, previous ischemic heart disease, smoking, and fewer implicated coronary arteries. Women presented with more atypical symptoms as compared to men (26.3% vs 19.4%, p = 0.017). Overall multivariable-adjusted 30 day mortality was higher in women than in men (OR 2.47 95% CI 1.19-5.1, p = 0.015). Among patients with ST-elevation myocardial infarction (STEMI) or non-STEMI, women had a higher 10 year mortality rate than men (42.5% vs 19.2%, log-rank p < 0.001 and 31.5% vs 20.7%, log-rank, p = 0.012). However, in patients with unstable angina pectoris on admission, these differences were not seen (16.9% vs 13.4%, log-rank p = 0.540). Multivariable analysis demonstrated that female gender was a significant predictor for 10 year mortality (HR 1.39, 95% CI 1.02-1.9, p = 0.038). In a real-life setting, women constitute an independent predictor for short- and long-term mortality following ACS treated by CABG surgery. The reasons for a higher mortality in women should be further investigated as well as specific and/or more intensive therapies after CABG in this high-risk group of patients.

      Graphical abstract

      Keywords

      Abbreviations:

      CABG (Coronary artery bypass grafting), ACS (Acute coronary syndrome), ACSIS (Acute Coronary Syndrome Israeli Survey), MI (Myocardial infarction), HR (Hazard ratio), CI (Confidence interval), NSTEMI (Non ST-segment elevation myocardial infarction), STEMI (ST-segment elevation myocardial infarction), UAP (Unstable angina pectoris), PCI (Percutaneous coronary intervention), CAD (Coronary artery disease), MACE (Major adverse cardiovascular events)
      Unlabelled image
      Hazard plot for survival at 10 years by gender, with propensity score adjustment.
      Central Message
      In a real-life setting, women constitute an independent predictor for short- and long-term mortality following ACS treated by CABG surgery.
      Perspective Statement
      Female gender presenting with acute coronary syndrome represents a high-risk population for CABG. Further studies are needed to examine the factors influencing prognosis in women after CABG and whether novel interventions and tight risk-factor control, can improve their outcome.

      INTRODUCTION

      The impact of gender on clinical outcomes after coronary artery bypass grafting (CABG) has been reported in several studies, with controversial and non-definitive results.
      • Woods S.E.
      • Noble G.
      • Smith J.M.
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      The influence of gender in patients undergoing coronary artery bypass graft surgery: An eight-year prospective hospitalized cohort study.
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      Operative mortality in women and men undergoing coronary artery bypass grafting (from the California Coronary Artery Bypass Grafting Outcomes Reporting Program).
      Since the introduction of CABG numerous studies have shown that female gender has an adverse effect on patients undergoing CABG regarding mortality, morbidity and overall complications.
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      Impact of gender on coronary bypass operative mortality.
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      Gender differences in mortality rates for coronary artery bypass surgery.
      According to the Society of Thoracic Surgeons National Adult Cardiac Surgery database, women have an operative mortality of 3.5% compared to 2.1% for men.
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      • et al.
      Gender-specific practice guidelines for coronary artery bypass surgery: Perioperative management.
      Furthermore, over the last four decades age adjusted mortality for cardiovascular disease has steadily declined, albeit to a lesser extent in women than in men.
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      • et al.
      Trends in acute myocardial infarction in young patients and differences by sex and race, 2001 to 2010.
      In addition, studies have consistently demonstrated less favorable outcomes in women with acute coronary syndrome (ACS) compared to men.
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      Outcomes of different revascularization strategies among patients presenting with acute coronary syndromes without ST elevation.
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      • et al.
      Sex differences in outcomes after STEMI: Effect modification by treatment strategy and age.
      Susceptibility of women to adverse outcomes following ACS has been attributed to their older age at presentation, a higher prevalence of co-morbidities, as well as longer system delays and under-utilization of guideline-directed therapies.
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      • et al.
      Temporal trends analysis of the characteristics, management, and outcomes of women with acute coronary syndrome (ACS): ACS Israeli Survey Registry 2000-2016.
      However, other studies have shown no outcome differences between the sexes in ACS patients.
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      Gender differences in clinical and angiographic outcomes after coronary artery bypass surgery.
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      Gender influence in isolated coronary artery bypass graft surgery: a propensity match score analysis of early outcomes.
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      In this study we investigated the impact of gender on CABG performed following ACS, with respect to 30 day mortality, complications and late survival.

      METHODS

      Study Design

      The ACS Israeli Survey (ACSIS) is a voluntary biennial prospective national registry of all patients with ACS, including non-ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction (STEMI) or unstable angina pectoris (UAP). Our study cohort included ACS patients hospitalized in the 25 coronary care units and cardiology departments in all the public health hospitals in Israel over a 2 month period (from March to April) between 2000 to 2016.
      • Behar S.
      • Battler A.
      • Porath A.
      • et al.
      A prospective national survey of management and clinical outcome of acute myocardial infarction in Israel, 2000.
      ACSIS is managed by the Working Group on Acute Cardiovascular Care of the Israel Heart Society, in participation with the Israeli Center for Cardiovascular Research. Demographic, historical, and clinical data from all patients were recorded on pre specified forms. Patient management was at the discretion of the attending physicians. Admission and discharge diagnoses were recorded as determined by the attending physicians based on clinical, electrocardiographic, and biochemical criteria. This study was approved by the Institutional Review Board (IRB 4486-17-SMC) and all patients signed an informed consent form prior to participating in the ACSIS registry.
      • Kornowski R.
      The ACSIS Registry and primary angioplasty following coronary bypass surgery.

      Study Population

      The current study includes only patients who were hemodynamically stable, without any mechanical support prior to operation, and underwent a non-emergent surgery. Exclusion criteria included all patients who had undergone prior CABG, those who had moderate or severe valvular disease and pregnant or nursing women. Between 2000 and 2016 (which included 8 consecutive registries), 15,211 patients were hospitalized with ACS and were included in the ACSIS registry. Of them, 9378 (62%) underwent percutaneous revascularization and 4525 patents (29%) were treated conservatively, and therefore were excluded from this study. The study included the remaining 1308 patients who underwent CABG: 1045 (80%) were men and 263 (20%) were women (Fig. 1), with similar distribution between the different centers (Supplemental Fig. 1).
      Figure 1
      Figure 1Flow chart summarizing eligibility through follow-up. Among the 15,211 ACS patients included in the registry, 1308 underwent surgical revascularization; 1045 (80%) were men and 263 (20%) were women.
      ACS, Acute coronary syndrome; NSTEMI, Non-ST-elevation myocardial infarction; PCI, Percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; UAP, Unstable angina pectoris.

      Clinical Outcomes

      Clinical outcomes included 30 day all-cause mortality, recurrent myocardial infarction (MI), stroke and long-term all-cause mortality.

      Data Collection and Follow-Up

      All data from the 25 participating hospitals were collected and pooled into a designated database. All centers used standardized definitions for data collection, including demographic parameters, medical history, chronic and peri procedural medical treatment, echocardiography measurements, procedure information and outcome measures. All patients were prospectively followed up for clinical events at 30 days and for late mortality. Mortality data were ascertained from the Israeli Ministry of Interior Population Register through January 2018 and was completed for all patients.

      Statistical Analysis

      Continuous variables were tested using the Kolmogorov-Smirnov test for distribution and are presented as mean ± standard deviation, if normally distributed, and as median (interquartile range), if non-normally distributed. Categorical variables are given as frequencies and percentages. A chi-square test was used for comparison of categorical variables between the genders. A Student's t-test was performed for comparison of normally distributed continuous variables and Mann-Whitney U test for non-normal distribution.
      Multivariable logistic regression analysis was used to identify factors associated to 30 day mortality. All statistically different variables (p < 0.1) in Table 1 and pre-specified variables were entered into the model. Multivariable Cox regression analysis was used to identify factors associated with mid-term mortality (1 and 5-year, Supplemental Tables 1 and 2). Additional Cox proportional hazard model was constructed to assess the association between gender and 10 year mortality adjusted to the following covariates: age, hypertension, dyslipidemia, smoking, diabetes mellitus, renal impairment, prior MI, body mass index, prior stroke, and congestive heart failure. Variables were selected as described above. Results are presented as hazard ratio (HR), 95% confidence interval (CI) and p value. Long-term survival analysis, in the subgroups of STEMI, NSTEMI and UAP, was carried out using the Kaplan-Meier method, and comparison between men and women was tested using the log-rank test.
      Table 1Patient Characteristics.
      Male

      No. of patients

      (1045) (%)
      Female

      No. of patients

      (263) (%)
      p valueMissing data

      (%)
      Age, years (mean ± SD)63 ± 1170 ±10<0.0010
      Hypertension601 (58)186 (71)<0.0010.1
      Diabetes mellitus645 (62)135 (51)0.0030.1
      Current smokers408 (39)36 (14)<0.0010.6
      Dyslipidemia696 (67)190 (72)0.0970.5
      COPD38 (4)10 (4)1.0000
      Family history of CAD254 (24)54 (21)0.2110
      BMI (kg/m2) [median (IQR)]26.9 (24.6-29.7)27.6 (24.4-31.2)0.1794.8
      Prior MI308 (30)59 (22)0.0250.4
      Prior PCI268 (26)45 (17)0.0040.6
      Renal impairment85 (8)24 (9)0.5890.2
      Peripheral vascular disease96 (9)27 (10)0.6860.2
      Previous CVA/TIA85 (8)28 (11)0.2480.3
      Congestive heart failure57 (5)31 (12)<0.0010.3
      On-site cardiac surgery unit559 (53)133 (51)0.4360
      Prior medications
      Aspirin462 (44)129 (49)0.1410
      P2Y12 inhibitors58 (6)22 (8)0.1120
      ACE-I187 (18)58 (22)0.1010
      ARBs51 (5)23 (9)0.0190
      Beta blockers305 (29)109 (41)<0.0010
      Statins403 (39)125 (47)0.0070
      Calcium channel blockers167 (16)68 (26)<0.0010
      Nitrates101 (10)44 (17)0.0020
      Aldosterone receptor antagonist2 (1)2 (1)0.4120
      Diuretics96 (9)49 (19)<0.0010
      Post CABG medication
      Aspirin954 (93)225 (88)0.0131.9
      P2Y12 inhibitors233 (23)43 (17)0.0503.3
      ACE-I / ARBs663 (64)183 (70)0.0580.8
      Beta blockers754 (74)197 (78)0.3433.1
      Statins840 (83)202 (79)0.1902.8
      ACE-I, Angiotensin converting enzyme inhibitors; ARBs, Angiotensin II receptor blockers; BMI, Body mass index; CAD, Coronary artery disease; COPD, Chronic obstruction pulmonary disease; CVA, Cerebrovascular accident; IQR, Interquartile range; MI, Myocardial infarction; PCI, Percutaneous coronary intervention; SD, Standard deviation; TIA, Transient ischemic attack.
      Statistical significance was assumed when the null hypothesis could be rejected at p < 0.05. All p values reflect results of two-sided tests. Statistical analyses were conducted using R (version 4.0.3).

      RESULTS

      Baseline Characteristics

      Of the 1308 patients included in the study, 1045 (80%) were men and 263 (20%) were women. Among them 460 (35%) patients presented with STEMI, 587 (45%) with NSTEMI and 261 (20%) with UAP. After the diagnostic catheterization, 1131 (87%) patients underwent revascularization by CABG and 177 (13%) by both percutaneous coronary intervention (PCI) and CABG. The gender distribution was similar in both revascularization strategies, either by CABG alone (20% female) or by both PCI and CABG (18% female), and did not change significantly during the 8 data collection times during the 16 year study (Supplemental Fig. 2).
      Women were older and had more hypertension, hyperlipidemia and more prior congestive heart failure at baseline, although no sex differences were seen in baseline ejection fraction after ACS. The use of beta-blockers, calcium channel blockers, diuretics and statins were higher amongst women, with no sex differences seen in the use of anti-platelets therapy prior to CABG. Men were more likely to smoke, have diabetes mellitus, previous ischemic heart disease or prior PCI (Table 1). Atypical presenting symptoms, that did not include chest pain, was found more in women compared to men (26.3% vs 19.4%, p = 0.017). More extensive coronary artery disease (CAD) involving all 3 coronary vessels was seen in men as compared to women. There were no gender differences in the number of STEMI and NSTEMI events (Table 2). More men were discharged on anti-platelets therapy as compared to women with no significant sex differences seen in other therapies (Table 1).
      Table 2Categories of Acute Coronary Syndrome
      Male

      No. of patients

      (1045) (%)
      Female

      No. of patients

      (263) (%)
      p value
      ACS diagnosis0.173
       NSTEMI463 (45)124 (47)
       STEMI380 (36)80 (31)
       UAP202 (19)59 (22)
      Left ventricle ejection fraction0.449
       Normal (> 50%)324 (38)97 (42)
       Mild (40-50%)272 (32)63 (28)
       Moderate (30-40%)180 (21)50 (22)
       Severe (< 30%)82 (9)18 (8)
      Left ventricle ejection fraction [%, median (IQR)]45 (35-60)45 (35-65)0.193
      Number of CAD0.001
       1 Vessel43 (6)18 (10)
       2 Vessels166 (23)61 (34)
       3 Vessels509 (71)101 (56)
      Vital signs on admission
      Heart rate (bpm) [median (IQR)]80 (68-95)80 (70-95)0.288
      Systolic blood pressure (mmHg) [median (IQR)]140 (124-160)145 (130-170)0.009
      Diastolic blood pressure (mmHg) [median (IQR)]80 (70-91)79 (69-90)0.003
      Normal sinus rhythm823 (90)209 (92)0.537
      Atrial fibrillation/SVT34 (4)12 (6)0.362
      VT/VF6 (1)0 (0)0.480
      2nd-3rd-degree AV-Block6 (1)0 (0)0.499
      ACS, Acute coronary syndrome; AV, Atrioventricular; CAD, Coronary artery disease; IQR, Interquartile range; NSTEMI, Non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UAP, Unstable angina pectoris; SD, Standard deviation; SVT, Supraventricular tachycardia; VT, Ventricular tachycardia; VF, Ventricular fibrillation.

      Early and Mid-Term Outcomes

      Overall 30 day mortality was higher in women than in men: 8.4% vs 3.1% (p < 0.001). Other 30 day major events were similar between men and women, such as stroke (0.1% vs 0.4%, p = 0.865) and recurrent MI (1.6% vs 1.5%, p = 1.000). Multivariable logistic regression analysis demonstrated that women gender was an independent predictor for 30 day mortality after CABG (OR 2.47 95% CI 1.19-5.1, p = 0.015). Additional predictors for 30 day mortality included older age (Table 3).
      Table 3Multivariable Logistic Regression Analysis Predictors for 30 day All-Cause Mortality.
      OR95% CIp value
      Sex (female)2.471.19-5.10.015
      Age1.081.04-1.13<0.001
      Diabetes1.430.71-30.328
      Hypertension1.160.53-2.670.709
      Previous MI1.30.48-3.290.595
      Previous PCI0.480.14-1.410.208
      CHF0.850.18- 2.970.814
      Hyperlipidemia0.920.42-20.824
      Three-vessel CAD1.230.62-2.550.564
      Smoking1.510.66- 3.30.315
      Statin therapy0.60.26-1.390.231
      Beta blockers0.880.4-1.90.746
      Calcium channel blocker therapy0.630.26-1.440.294
      Diuretics0.920.33-2.310.870
      Nitrate usage1.270.45-3.170.631
      ARBs1.290.58-2.780.516
      ARBs, Angiotensin II receptor blockers; CAD, Coronary artery disease; CI, Confidence interval; CHF, Congestive heart failure; HR, Hazard ratio; MI, Myocardial dysfunction; OR, Odds ratio; PCI, Percutaneous coronary intervention.
      The multivariable-adjusted 1 and 5-year mortality hazard was higher among women than in men (16.9% vs 7.3%, HR 1.68 95% CI 1.04-2.7, p = 0.034 and 22.4% vs 11.8%, HR 1.56 95% CI 1.04-2.35, p = 0.031) (Supplemental Tables 1 and 2).

      Long-Term Mortality

      The median follow-up duration of the entire cohort was 8 years (3.1-11.7 years). Comparison between women and men regarding late mortality revealed a 40% higher mortality in women (Fig. 2). The propensity score adjusted 10 year mortality rates were higher in women than in men: 31.6% vs 18.8% (HR 1.39 95% CI 1.04-1.85, p = 0.028) (Fig. 2). Multivariable analysis demonstrated that predictors for 10 year mortality were: female gender, age > 65 years, diabetes mellitus, hypertension, dyslipidemia, higher body mass index, and renal impairment (Table 4).
      Figure 2
      Figure 2Hazard plot for survival at 10 years by gender, with propensity score adjustment*. Comparison between women and men regarding late mortality revealed a 40% higher mortality in women.
      * The covariates included in the model were: age, hypertension, dyslipidemia, smoking, diabetes mellitus, renal impairment, prior PCI, prior stroke, peripheral vascular disease, congestive heart failure, and discharge medication (aspirin, P2Y12 inhibition, ACE-I or ARB).
      ACE-I, Angiotensin converting enzyme inhibitors; ARB, Angiotensin II receptor blockers HR, Hazard ratio; PCI, Percutaneous coronary intervention.
      Table 4Multivariable Cox Regression Analysis Predictors for 10 Year All-Cause Mortality
      HR95% CIp value
      Sex (female)1.391.02-1.90.038
      Age > 65 years2.261.63-3.15<0.001
      Diabetes mellitus1.331.01-1.750.043
      Hypertension1.681.21-2.340.002
      Dyslipidemia1.611.22-2.130.001
      Current smoker1.010.72-1.40.967
      Body mass index0.970.94-1.000.039
      Renal impairment1.541.03-2.270.033
      Prior myocardial infarction1.210.9-1.640.207
      Prior CVA/TIA0.930.61-1.410.717
      History of CHF1.160.73-1.840.543
      Discharge aspirin1.20.73-1.990.475
      Discharge P2Y12 inhibitor1.030.75-1.430.836
      Discharge ACE-I or ARBs0.840.63-1.120.224
      ACE-I, Angiotensin converting enzyme inhibitors; ARB, Angiotensin II receptor blockers; CI, Confidence interval; CVA, Cerebrovascular accident; CHF, Congestive heart failure; HR, Hazard ratio; TIA, Transient ischemic attack.

      Subgroup Analyses

      The proportion of male and/or female did not change significantly across the different subgroups who underwent surgery: among the 460 patients presented with STEMI, 380 (83%) were male and 80 (17%) female; among the 587 patients presented with NSTEMI, 463 (79%) were male and 124 (21%) female; and among the 261 patients presented with UAP, 202 (77%) were male and 59 (23%) were female (p = 0.173).
      The peak troponin T levels were similar between male and female both in patients presented with STEMI (1.52 [0.35-5.23] ng/ml vs 1.39 [0.35-4.88] ng/ml, p = 0.781) and NSTEMI (0.35 [0.13-1.55] ng/ml vs 0.51 [0.12-1.16] ng/ml, p = 0.898).
      The median follow-up duration was 9.5 years (4.5-12.3 years) for patients admitted with STEMI, 6.5 years (1.8-10.9 years) for patients admitted with NSTEMI, and 9.5 years (4.5-13.4 years) for patients admitted with UAP. Among patients who presented with STEMI or NSTEMI on admission, women compared to men had higher 30 day mortality (15% vs 3.4%, p < 0.001 and 8.1% vs 3%, p = 0.023 respectively), and higher 10 year mortality (42.5% vs 19.2%, log-rank p < 0.001 and 31.5% vs 20.7%, log-rank p = 0.012 respectively). However, among patients who presented with UAP these sex differences were not seen (30 day mortality: 0% vs 2.5%, p = 0.496; 10 year mortality: 16.9% vs 13.4%, log-rank p = 0.540) (Fig 3).
      Figure 3
      Figure 3Kaplan Meier curves for survival by gender among patients admitted to hospital with acute coronary syndrome: STEMI, NSTEMI and unstable angina pectoris. We showed that women who presented with STEMI or NSTEMI had higher rates of long-term mortality. In contrast, among patients presenting with unstable angina pectoris no sex differences were seen in late survival.
      NSTEMI, Non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.
      Figure 3
      Figure 3Kaplan Meier curves for survival by gender among patients admitted to hospital with acute coronary syndrome: STEMI, NSTEMI and unstable angina pectoris. We showed that women who presented with STEMI or NSTEMI had higher rates of long-term mortality. In contrast, among patients presenting with unstable angina pectoris no sex differences were seen in late survival.
      NSTEMI, Non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

      DISCUSSION

      Our observational real-world study investigated the impact of gender on early and late mortality in ACS patients treated by CABG. We showed that women who presented with STEMI or NSTEMI ACS had higher rates of short- and long-term mortality. In contrast, among patients presenting with UAP and undergoing CABG no sex differences were seen in outcomes (Fig. 4 and Graphical abstract). There are several distinguishing factors between men and women regarding cardiovascular disease and potential different outcomes after ACS and CABG.
      Figure 4
      Figure 4A graphical summary of the main findings of the study. Women who presented with STEMI or NSTEMI ACS had higher rates of short- and long-term mortality.
      ACS, Acute coronary syndrome; NSTEMI, Non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

      Gender Differences in Coronary Anatomy and Function

      Women were shown to have significantly smaller epicardial coronary arteries than men, even after adjustment for age, body habitus, and left ventricular mass.
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      Smaller coronary arteries coupled with higher myocardial perfusion or coronary blood flow
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      Heart rate reserve during pharmacological stress is a significant negative predictor of impaired coronary flow reserve in women.
      (both at rest and during hyperemia) have been linked to clinically significant higher endothelial shear stress seen in women. As a consequence, diverse and sex-specific pathophysiological processes may contribute to different IHD phenotypes seen in women as compared to men. Women present with more eccentric plaques and endothelial dysfunction than men
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      and while plaque rupture is the primary mechanism responsible for MI in men, plaque erosion is the major cause of coronary thrombosis in women, particularly in premenopausal women.
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      Cardiovascular Risk Factors and ACS

      Although traditional risk factors for cardiovascular disease are the same in both men and women, differences in the prevalence and impact of these risk factors vary between the sexes.
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      • Manson J.E.
      Cardiovascular Disease in Women: Clinical Perspectives.
      Furthermore, sex-specific risk factors for cardiovascular disease as adverse pregnancy outcomes, early menopause and specific cancer therapies can influence a woman's cardiovascular risk, phenotype of IHD and its aggressiveness.
      Systolic blood pressure rises steeply in older women and although hypertension was associated with more cardiovascular complications in women as compared to men, no sex differences were seen in relation to hypertension major adverse cardiovascular events (MACE) in a recent meta-analysis.
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: a systematic review and meta-analysis of 124 cohort studies, including 1.2 million individuals.
      Similarly, lipid profile worsens in women post-menopause but the risk of MACE in relation to total cholesterol was similar in women as compared to men.
      • Peters S.A.
      • Singhateh Y.
      • Mackay D.
      • Huxley R.R.
      • Woodward M.
      Total cholesterol as a risk factor for coronary heart disease and stroke in women compared with men: A systematic review and meta-analysis.
      Despite similar prevalence in both genders diabetes seems to diminish any cardioprotective effect of younger age in women.
      • Peters S.A.
      • Huxley R.R.
      • Woodward M.
      Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events.
      Furthermore smoking is more harmful in women as compared to men with a higher risk of MACE seen in women.
      • Huxley R.R.
      • Woodward M.
      Full hazards of smoking and benefits of stopping for women.
      Most studies showed a higher burden of co-morbidities in women presenting with ACS, most probably linked also to older age at presentation. The key to reduce the risk of morbidity and mortality following ACS treated by CABG is a secondary prevention plan, that should include specific recommendations for post hospitalization care include a cardiac rehabilitation program, and tight risk-factor control. We believe that these elements are even more crucial in females due to the worsen outcomes.

      Differences in Presentation Between Men and Women

      We reported that in this cohort women presented with more atypical symptoms, without any chest pain, as compared to men. A finding that may explain the different outcomes between the genders in patients who presents with STEMI/NSTEMI, but not with UAP. While chest pain is the presenting symptom in most men and women with ACS, women present with a greater number of additional non-chest pain symptoms than men, such as neck pain, fatigue, or nausea, and are therefore more likely to present without chest pain, often attributing their symptoms to a non-heart-related condition.
      • Lichtman J.H.
      • Leifheit E.C.
      • Safdar B.
      • et al.
      Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO Study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
      Furthermore, some studies have shown that women, compared to men, are less likely to have diagnostic electrocardiography changes and elevated troponin levels on admission, subsequently leading to delayed diagnosis.
      • Canto J.G.
      • Goldberg R.J.
      • Hand M.M.
      • et al.
      Symptom presentation of women with acute coronary syndromes: Myth vs reality.
      • Meyer M.R.
      • Bernheim A.M.
      • Kurz D.J.
      • et al.
      Gender differences in patient and system delay for primary percutaneous coronary intervention: current trends in a Swiss ST-segment elevation myocardial infarction population.
      • Roswell R.O.
      • Kunkes J.
      • Chen A.Y.
      • et al.
      Impact of sex and contact-to-device time on clinical outcomes in acute ST-segment elevation myocardial infarction-findings from the national cardiovascular data registry.
      • Sabbag A.
      • Matetzky S.
      • Porter A.
      • et al.
      Sex differences in the management and 5-year outcome of young patients (<55 Years) with Acute Coronary Syndromes.
      Other studies have shown that ACS patients who present with atypical complaints have a less favorable outcome compared with patients who present with typical chest pain.
      • Hammer Y.
      • Eisen A.
      • Hasdai D.
      • et al.
      Comparison of Outcomes in patients with acute coronary syndrome presenting with typical versus atypical symptoms.
      Women also tend to receive less guideline- based medical therapy for their risk factors
      • Herscovici R.
      • Sedlak T.
      • Wei J.
      • Pepine C.J.
      • Handberg E.
      • Bairey Merz C.N.
      Ischemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk?.
      or after an ACS
      • Mehta L.S.
      • Beckie T.M.
      • DeVon H.A.
      • et al.
      Acute myocardial infarction in women: A scientific statement from the American heart association.
      which might also contribute to worse prognosis. Only fifth of the women in the current cohort received dual anti-platelet therapy and fifth were discharged with no statin therapy.
      Given women appear to present at an older age and with more co-morbidities and often have atypical chest pain, there is a benefit to having a higher index of suspicion for cardiovascular disease and a lower threshold for more aggressive diagnostic studies and earlier intervention in women. Potential ways of improving their outcome after CABG may include cardiac rehabilitation program, tight risk-factor control, and timely follow-up.

      Surgical Differences Between Men and Women

      Although the left internal mammary artery is used in a similar percentage of patients of both sexes, and total arterial revascularization is performed in similar numbers in both sexes, men undergo significantly more bypass grafts.
      • Nicolini F.
      • Vezzani A.
      • Fortuna D.
      • et al.
      Gender differences in outcomes following isolated coronary artery bypass grafting: long-term results.
      This may indeed influence the long-term survival advantage of men. Unfortunately, anatomical information regarding the complexity of CAD and the surgical techniques performed were lacking in the ACSIS registry.
      An interesting finding of this study was that both men and women who underwent CABG had similar ejection fractions after ACS (Table 2). This finding is contrary to a recent study by Berton et al who showed that women have more heart failure after an acute MI.
      • Berton G.
      • Cordiano R.
      • Cavuto F.
      • Bagato F.
      • Pellegrinet M.
      • Cati A.
      Heart failure in women and men during acute coronary syndrome and long-term cardiovascular mortality (the ABC-3* Study on Heart Disease) (*Adria, Bassano, Conegliano, and Padova Hospitals).
      This finding is important because of the recognized survival advantage of women over men in patients with congestive heart failure with reduced left ventricle ejection fraction.
      • Adams Jr., K.F.
      • Sueta C.A.
      • Gheorghiade M.
      • et al.
      Gender differences in survival in advanced heart failure. Insights from the FIRST study.
      ,
      • Martinez-Selles M.
      • Doughty R.N.
      • Poppe K.
      • et al.
      Gender and survival in patients with heart failure: Interactions with diabetes and aetiology. Results from the MAGGIC individual patient meta-analysis.
      Similarly, the burden of age and comorbidities may influence differently women and men undergoing major surgery as CABG and as a consequence the development of surgery related complications might differ among sexes. The intensity of post -CABG therapy was different in women as compared to men, another factor that might contribute to different outcomes.

      Limitations

      Primarily, the ACSIS registry included patients admitted only to cardiology wards and intensive cardiac care units nationwide, thus introducing a selection bias. The ACSIS registry include only patients who agreed to participate in the registry, information on the number of patients who did not participate is lacking. There was insufficient anatomical information regarding the complexity of CAD, the specific artery involved, and the surgical techniques performed. Therefore, it is difficult to draw conclusions regarding the association between specific interventions in native arteries or grafts and clinical outcomes. The registry did not record any surgical preoperative risk assessment score. This might have provided a more comprehensive assessment of individual patient risk and how the two genders compare. There were substantial differences between the sexes in our cohort. We attempted to overcome some of the clinical differences by statistical adjustment of important variables. We had no information regarding the main cause of death or the rate of cardiac events, such as recurrent revascularization, and MI during the follow-up period beyond 30 days. Additional factors (other than cardiovascular) may have contributed to the higher mortality in women.

      CONCLUSIONS

      In a real-life setting, female gender represents an independent predictor for short- and long-term mortality following ACS treated by CABG. This high-risk population may require specific and/or more intense cardiovascular protective therapies after CABG, such as cardiac rehabilitation program, tight risk-factor control, and timely follow-up. Further studies are needed to examine the factors influencing prognosis in women after CABG and whether novel interventions can improve their outcome.

      Supplementary Material

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