Long-Term Prognostic Impact of Sex in Patients with Chronic Coronary Syndrome: A 17-Year Prospective Cohort Study

Abstract

Background:

Women and men with chronic coronary syndrome (CCS) have different clinical features and management, and studies on mid-term prognosis have reported conflicting results. Our objective was to investigate the impact of the female sex in the prognosis of the disease in the very long term.

Methods and Results:

We investigated differential features and very long-term prognosis in 1268 consecutive outpatients with CCS (337 [27%] women and 931 [73%] men). Women were older than men, more likely to have hypertension, diabetes, angina, and atrial fibrillation, and less likely to be exsmoker/active smoker and to have been treated with coronary revascularization (p < 0.05 for all). The prescription of statins, antiplatelets, and betablockers was similar in both groups. After up to 17 years of follow-up (median = 11 years, interquartile range = 4–15 years), cumulative incidences of acute myocardial infarction (10.2% vs. 11.8%) or stroke (11% vs. 10%) at median follow-up were similar, but the risks of major cardiovascular events (acute myocardial infarction, stroke, or cardiovascular death, 41.2% vs. 33.6%), hospital admission for heart failure (20.9% vs. 11.9%), or cardiovascular death (32.3% vs. 22.1%) were significantly higher for women (p < 0.0005), with a nonsignificant trend to higher overall mortality (45.2% vs. 39.1%, p = 0.07). However, after multivariate adjustment, all these differences disappeared.

Conclusion:

Although women and men with CCS presented a different clinical profile, and crude rates of major cardiovascular events, heart failure and cardiovascular death were higher in women, female sex was not an independent prognostic factor in this study with up to 17 years of follow-up.

Introduction

Cardiovascular diseases are the first cause of mortality worldwide,¹ both in men and women, and coronary artery disease is the most frequent manifestation. Previous studies have shown that clinical features and management of coronary disease are different in women and men, both in acute coronary syndrome (ACS) and in chronic coronary syndrome (CCS).^2

–5 In general, women with CAD are older than men, with a worse cardiovascular risk factor profile, and usually receive less revascularization and optimal medical treatment.^2

–6 However, studies on the impact of sex on prognosis have shown conflicting results, with some of them with similar outcomes for both sexes^{3,4,7

–12} but not all.^13

–18 Even more, most of these studies have reported limited periods of follow-up^{2
–4,7

–21} and there are no data on the very long-term (>6 years) impact of the female sex in cardiovascular events and mortality in patients with CCS.

The CICCOR registry (Chronic ischemic heart disease in Córdoba, in Spanish, Cardiopatía Isquémica Crónica en CÓRdoba) is a prospective, monocentric, observational, cohort study whose aim is to investigate the prognosis of CCS, with up to 17 years of follow-up.^22

–27 The objective of the present work was to analyze the differential features and cardiovascular outcomes in women and men in the very long term in patients with CCS, using the CICCOR database.

Methods

Study design and patients

The rationale, design, baseline characteristics, and some specific outcomes of the CICCOR registry have been previously reported.^22

–27 From January 2000 to February 2004, the study prospectively included all patients with CCS who were attended at two general cardiology outpatient offices at a university hospital in the south of Spain, referred by primary care physicians, emergency departments, or for a check-up after hospitalization in cardiology or internal medicine wards.

Patients were eligible for the study when CCS was present, defined by one or more of the following inclusion criteria: (a) history of ACS (unstable angina or acute myocardial infarction) or surgical or percutaneous coronary revascularization at least 3 months before inclusion; (b) history of chest pain with a stress test, myocardial perfusion imaging, or stress echocardiogram consistent with ischemia; or (c) coronary angiography with stenosis >70% of the luminal diameter of an epicardial vessel, with no severe valve disease. Patients were excluded only if they declined to participate in the study. The study was performed in accordance with ethical principles that are consistent with the Declaration of Helsinki, all patients granted informed consent for inclusion and follow-up, and the CICCOR registry protocol was approved by the local Ethics Committee for clinical investigation of Córdoba.

Data collection and definition of events

Information on demographics, medical history, physical examination, and additional tests was collected at the first appointment. Abnormal electrocardiogram was defined as the presence of right or left bundle branch block, pathologic Q wave, ST segment depression >1 mm, or negative T wave in two or more contiguous leads. Cardiomegaly was considered if the cardiothoracic ratio was >0.5 in a previously performed posteroanterior chest radiograph. Patients received treatment and follow-up at the discretion of their attending cardiologists in accordance with the clinical practice guidelines of the scientific societies in effect at the time.^28
–30

Data on the follow-up were updated for each patient between June 1, 2016 and December 31, 2016. The data search included medical histories, primary care contact, and telephone interviews when necessary to minimize losses on the follow-up. Events registered in follow-up were: acute myocardial infarction, stroke, heart failure admission, cardiovascular death, all-cause death, and a composite outcome of major cardiovascular events (MACE: acute myocardial infarction, stroke, or cardiovascular death).

Myocardial infarction was defined according to the universal definition,³¹ and only type 1, 3, 4, and 5 were considered to be endpoints in the present analysis. A stroke was defined as a neurological focal deficit of sudden onset, diagnosed by a neurologist after a brain imaging study, as stated in the patient's medical records. Heart failure admission was defined as at least one-night hospital stay for symptoms of dyspnea or edema, along with bilateral rales, elevated venous pressure, congestion signs on a chest X-ray, or the use of intravenous diuretics or inotropic drugs. Cardiovascular death was considered to be death caused by ACS, acute aortic syndrome, heart failure, or stroke. Also, those deaths without a clear noncardiovascular cause were assumed to be of cardiovascular origin, as other previous studies have considered.^32,33 Events were accepted as reported by physicians and were not adjudicated.

Statistical analyses

Baseline features of the whole population and comparative analysis by sex were expressed using mean ± standard deviation for quantitative data, after checking for the normality of the distributions with the Kolmogorov–Smirnoff test, and number and percentages for qualitative variables. Comparison of variables between women and men were performed with Student's t-test for quantitative data and Chi-square tests for categorical variables, using Fisher's exact test if necessary.

Cumulative incidence of major cardiovascular events, acute myocardial infarction, stroke, heart failure admission, and cardiovascular death were calculated considering death without the event as a competing risk, and curves were constructed separately for women and men, and compared with Gray's test.³⁴ For all-cause death, Kaplan–Meier analysis and log-rank test were used.

Associations of the female sex with each of the events of interest were investigated by univariate and multivariate Cox proportional hazards analysis, adjusted for baseline differences (age, cardiovascular risk factors, previous medical history, symptoms of angina, heart rate, and medical treatment). The proportional hazards assumption was verified by a plot method (logarithm-minus-logarithm plots). The results were expressed as hazard ratios (HR) with the respective 95% confidence intervals (95% CI). Cumulative incidence curve calculations were performed with R statistical software³⁴ with the cmprsk package.³⁶ All other statistical analyses were performed using IBM SPSS Statistics, version 21.0 (IBM Corp., Armonk, New York).

Results

Differential features by sex

A total of 1268 patients were included in the study, with 337 being women (27%). Differential features by sex are shown in Table 1. Women with CCS in our series were older than men, more likely to have hypertension and diabetes and less likely to be exsmokers /active smokers. They had more frequently angina in functional class ≥II, heart failure, and atrial fibrillation, but had received less frequently coronary revascularization. On the other hand, we did not find any differences in the frequency of hypercholesterolemia, family history of coronary disease, prior ACS, previous stroke, blood pressure, and complementary tests results. Prescription of statins, antiplatelets, anticoagulants, and betablockers at the first visit was similar to men, but women received more frequently nitrates, digoxin, angiotensin-converting enzyme inhibitors or receptor antagonists, calcium channel blockers, and diuretics.

Table 1.

Baseline Characteristics of Our Cohort, Differential Features, and Events in Follow-Up of Women and Men in the Series

Variables	Total N = 1.268	Women N = 337 (27%)	Men N = 931 (73%)	p
Demographics
Age (years)	66.73 ± 10.45	70 ± 9	65 ± 11	<0.001
Cardiovascular risk factors
Hypertension	697 (55%)	243 (72.1%)	454 (48.8%)	<0.001
Diabetes mellitus	394 (31.1%)	153 (45.4%)	241 (25.9%)	<0.001
Hypercholesterolemia	985 (77.7%)	254 (75.4%)	731 (78.5%)	0.249
Current smoker	83 (6.5%)	5 (1.5%)	78 (8.4%)	<0.001
Exsmoker	463 (36.5%)	17 (5%)	446 (47.9%)	<0.001
Family history of coronary disease	103 (8.1%)	21 (6.2%)	82 (8.8%)	0.124
Previous medical history
Prior acute coronary syndrome	1049 (82.7%)	281 (83.4%)	768 (82.5%)	0.794
Prior revascularization	512 (40.4%)	107 (31.8%)	405 (43.5%)	<0.001
Previous heart failure	56 (4.4%)	22 (6.5%)	34 (3.7%)	0.028
Previous stroke	28 (2.2%)	10 (3%)	18 (1.9%)	0.28
Atrial fibrillation	70 (5.5%)	26 (7.7%)	44 (4.7%)	0.042
Symptoms
Angina Functional Class ≥II	231 (18.2%)	74 (22%)	157 (16.9%)	0.039
Physical exam at first visit
Heart rate (beats per minute)	67.65 ± 11.3	69.03 ± 11.16	67.15 ± 11.32	0.009
Systolic blood pressure (mmHg)	129.45 ± 15.78	130.28 ± 16.6	129.15 ± 15.47	0.265
Diastolic blood pressure (mmHg)	74.12 ± 8.96	73.64 ± 8.79	74.29 ± 9.01	0.261
Complementary tests
Abnormal electrocardiogram	771 (60.8%)	205 (60.8%)	566 (60.8%)	0.888
Left ventricular ejection fraction	56.22 ± 3.6	56.65 ± 13.88	56.06 ± 13.52	0.566
Cardiomegaly in chest plain film	119 (9.4%)	36 (10.7%)	83 (8.9%)	0.426
Medical treatment at first visit
ACEI/ARB II	620 (48.9%)	188 (55.8)	432 (46.4%)	0.004
Statins	846 (66.7%)	216 (64.1%)	630 (67.7)	0.224
Beta blockers	810 (63.9%)	224 (66.5%)	586 (62.9%)	0.277
Oral anticoagulation	65 (5.1%)	23 (6.8%)	42 (4.5%)	0.101
Antiplatelets	1160 (91.5%)	301 (89.3%)	859 (92.3%)	0.074
Digoxin	49 (3.9%)	19 (5.6%)	30 (3.2%)	0.048
Nitrates	853 (67.3%)	262 (77.7%)	591 (63.5%)	<0.001
Calcium channel blockers	576 (45.4%)	168 (49.9%)	408 (43.8%)	0.053
Diuretics	343 (27.1%)	138 (40.9%)	205 (22%)	<0.001

Events in follow-up					Crude HR (CI 95%)	Adjusted HR ^a (CI 95%)	p^a
Acute myocardial infarction	167 (13.2%)	40 (11.9%)	127 (13.7%)	0.55	0.90 (0.63–1.28)	0.79 (0.55–1.14)	0.21
Stroke	152 (12.0%)	44 (13.1%)	108 (11.6%)	0.40	1.17 (0.82–1.67)	0.88 (0.61–1.28)	0.52
Major cardiovascular events	525 (41.5%)	158 (47.0%)	367 (39.5%)	0.02	1.24 (1.03–1.50)	0.87 (0.7–1.1)	0.23
Hospital admission for heart failure	203 (16.0%)	83 (24.7%)	120 (12.9%)	<0.0005	2.02 (1.53–2.67)	1.11 (0.8–1.54)	0.52
Cardiovascular death	375 (29.6%)	128 (38.1%)	247 (26.6%)	<0.0005	1.51 (1.22–1.87)	0.92 (0.2–1.16)	0.47
All cause death	629 (49.7%)	180 (53.6%)	449 (48.3%)	0.07	1.17 (0.99–1.40)	0.83 (0.67–1.02)	0.08

All values are numbers and percentages, except if units are specified.

Adjusted for baseline differences between women and men (age, cardiovascular risk factors, previous medical history, symptoms of angina, heart rate, and medical treatment).

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CI, confidence interval; HR, hazard ratio.

Outcomes in follow-up

After up to 17 years of follow-up (median = 11 years, interquartile range = 4–15 years), with only two patients lost in follow-up and a total of 12,612 patient-years of observation, 167 patients had an acute myocardial infarction (13.2%), 152 patients suffered a stroke (12%), 203 patients were admitted to hospital for heart failure (16%), 375 died of cardiovascular causes (29.6%), 629 died of any cause (49.7%), and 525 patients presented a MACE (41.5%). The cumulative incidence of acute myocardial infarction (10.2% vs. 11.8%, p = 0.41) or stroke (11% vs. 10%, p = 0.54) at median follow-up were similar in women and men, but the risks of MACE (41.2% vs. 33.6%, p = 0.01), hospital admission for heart failure (20.9% vs. 11.9%, p < 0.0005), or cardiovascular death (32.3% vs. 22.1%, p < 0.0005) were significantly higher for women, with a nonsignificant trend to higher overall mortality (45.2% vs. 39.1%, p = 0.07). Cumulative incidence of noncardiovascular mortality was significantly lower in women than in men at median follow-up (12.8% vs. 17.2%, p = 0.01) (Fig. 1).

FIG. 1.

Probability of events in follow-up, according to sex. For all figures, dotted lines stand for women and solid lines for men. Death without the event has been considered a competing risk for cumulative incidence calculations. AMI, acute myocardial infarction; MACE, major cardiovascular events.

After multivariate adjustment by those baseline variables that were different between women and men, the female sex was not significantly associated with any of the events of interest (HR [95% CI]: 0.79 [0.55–1.14], p = 0.21 for acute myocardial infarction; 0.89 [0.61–1.29], p = 0.54 for stroke; 0.87 [0.70–1.10], p = 0.23 for MACE; 1.13 [0.82–1.57], p = 0.46 for admission for heart failure; and 0.92 [0.73–1.16], p = 0.48 for cardiovascular death), with a nonsignificant trend to lower overall mortality (HR = 0.83 [0.67–1.02], p = 0.08) (Table 1).

Discussion

The main findings of this study were: women had different basal features than men, with a worse cardiovascular risk factor profile, more frequent cardiovascular comorbidities but lower rates of revascularization; cumulative incidences of heart failure admission, MACE, and cardiovascular death were higher in women in the very long-term follow-up; and these differences in prognosis disappeared after adjusting for baseline variables.

Regarding basal features of the population, our results are in line with previous observational data. In most of them, women are older than men,^3
–5,15 with very few exceptions,² although the authors of this study remarked that this finding was unusual. It is known that coronary disease used to begin later in life for women, perhaps in relation to the protective effects of estrogen exposure,⁵ although this hypothesis is not uniformly accepted.³⁷ Older age is a well-established adverse prognostic factor in patients with CCS.^{4,7

–14,16

–19} Higher rates of hypertension and diabetes in women, that have been found in our study as well as in previous literature^2,3 could be related, at least partly, to this age difference.

Other studies have found higher frequencies of family history of premature CAD in women,³ a finding that we have not been able to confirm in our sample. However, in that study, this risk factor was present in 28.5% or the population, and only 8.1% of our series. The differences in tobacco use, with more women never-smokers than men in our series, are consistent with previous reports.^2,3 Hypertension, diabetes mellitus, and tobacco use have shown a significant adverse prognostic impact on patients with CCS.^{4,7,8,10

–14,16,17,19,21}

The finding of higher rates of atrial fibrillation or heart failure is not consistent in previous studies.^2,3 Atrial fibrillation prevalence is generally higher in men in the general population,³⁸ but this finding has not been observed in some cohort studies of patients with CCS.^2,3 Previous heart failure admission has also been inconsistently found to be more frequent in women with CCS in previous studies, with some of them reporting this finding³ but not others.² Probably, differences in age, cardiovascular risk factors, time and place of recruitment, and previous management could account, at least partly, for these differences. Atrial fibrillation and heart failure have been reported as independent prognostic factors in patients with CCS.^{4,8,11,12,14,18}

We have found a lower rate of previous revascularization in women than in men, and this finding is also reported in most previous studies.^2,3,5,6 The reasons for this difference in management are not clear. Previous studies have found that women with coronary symptoms could look for medical assistance less and later than men,⁵ physicians could be prone to underestimate symptoms in women because of more atypical presentation,^5,39 to indicate less coronary angiography,^3,5 and that the frequency of absence of significant coronary lesions is higher in the female sex.^5,6,39,40 However, guidelines' recommendation is to manage coronary disease in the same way, independently of sex³⁹ and acknowledge that more investigation is needed on appropriateness of indication of coronary angiography and revascularization in women.

Women had more symptoms of angina than men in our series, a finding also observed in previous studies.^2,3,14 Perhaps the lower rates of revascularization in women could be related to this issue. Angina has been found to be a significant prognostic marker, especially in patients with previous infarction,^{4,8,10,11,14,16} and most patients, both women and men, in our series had suffered a prior ACS. Also, we found higher baseline heart rate in women, as other previous studies have found.³ Baseline heart rate is a known prognostic factor in patients with coronary disease^{7,13,17,19,20} and even in the general population.⁴¹

Other studies have found higher figures of systolic blood pressure or left ventricular ejection fraction, or lower prevalence of previous acute myocardial infarction,³ but it has not been the case in our study. All three factors have been found to negatively impact prognosis in patients with CCS.^{7,8,10

–13,17,19} Although we did not find significant differences in prescription of drugs of prognostic value, as antiplatelets, statins, or beta-blockers in women and men, as other studies did,^3,6,40 it is noteworthy that the frequency of use in the whole series is low for current standards, and comparing to registries with a more recent period of recruitment.³ However, other series contemporary in inclusion period to our cohort show similar results.⁴²

We did not find significant differences in the incidence of acute myocardial infarction or stroke among women and men, a finding also reported by other investigators.^3,4,9,13,16 However, we found a clear higher rate of heart failure admission in the very long term in women with CCS. Previous studies with shorter (≤5 years) follow-up did not find this difference,^3,4,7,8,10 or did not report this event,² although other previous studies had also found a significantly higher rate of heart failure admission in women with CCS.^13,15,17 The results of the multivariate analysis show that the main explicative cause appears to be the basal differences in age, risk factors, cardiovascular comorbidities, and management. It is possible, as well, that suboptimal medical management could have provoked a large number of events that has made it easier to find differences among groups.

We also found higher rates of cardiovascular death in women and lower rates of noncardiovascular death, with a nonsignificant difference in overall mortality. The higher rate of cardiovascular death had not been previously reported,^{2,3,9,11,16,19} however, it did not remain after multivariate adjustment by basal characteristics, and so, was probably related to unbalanced distribution of prognostic variables between both sex groups. The same applies to the rate of MACE, as the main contributor to the differences was the incidence of cardiovascular death. The higher frequency of MACE in women found in our study is in contradiction with other previous works, which describe lower^14
–16,18 or similar^5,21 rates than men. It is possible, as well, that differences in baseline distribution of prognostic factor between both sexes could account for these findings. Finally, we did not find significant differences in overall mortality, as other previous investigations had reported,^2,3,12,17 although the lower rate of noncardiovascular death at 5 years had been previously described by Sorbets et al.⁴

The main strength in our work is the very long follow-up, wider than any previously reported for this population, which has been no longer than 6 years^{2
–4,7

–21} with a large number of events. By the other side, our work has some limitations. Some baseline characteristics, as, for instance, obesity and peripheral artery disease, were incompletely registered in the database and could not be reliably analyzed. We were not able, as well, to trace changes of medical treatment in follow-up, and so, could only include basal treatment in the multivariate adjustment.

Another concern is that only 27% of patients followed were women, and our work would have been more impactful if the percentage of women was similar to that of men. Although the investigators did their best to correctly classify the causes of death, the events were not adjudicated by an independent committee, as it has been the case in other registries.^3,4 Another limitation was that we did not know coronary anatomy in all cases, and so, the proportion of patients with nonobstructive coronary disease could not be assessed. Finally, our study was a monocentric one, and so, the generalization of results should be done cautiously.

In conclusion, we have found significant differences in baseline characteristics between women and men in this monocentric prospective cohort study, with higher rates of heart failure admission, cardiovascular death, and MACE in the very long-term follow-up in women, although this worse prognosis appears to be fully explained by the different distributions found in basal variables with prognostic impact.

Footnotes

Acknowledgment

This work was presented at the European Society of Cardiology Congress in 2020 and published just in abstract form in the European Heart Journal 2020; vol 41 (suppl 2), pg 3190 https://doi-org.proxy.library.vcu.edu/10.1093/ehjci/ehaa946.3190

Authors' Contributions

M.R.O. and C.S.F.: Conceptualization, methodology, formal analysis, investigation, project administration, writing––original draft preparation; J.J.S.F., L.M.H., L.B.M., C.O.L., E.R.P., M.D.O., A.R.A., F.E.M., J.L.A., F.C.Á., J.C.C.D., M.A.S., M.P., and D.M.R.: conceptualization, investigation, writing––review and editing; and all authors approved the final version of the article and agreed to send it for publication.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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