Sex Differences in Long-Term Outcomes in Patients With Chronic Coronary Syndrome After Percutaneous Coronary Intervention　― Insights From a Japanese Real-World Database Using a Storage System ―

Naoyuki Akashi; Tetsuya Matoba; Takahide Kohro; Yusuke Oba; Tomoyuki Kabutoya; Yasushi Imai; Kazuomi Kario; Arihiro Kiyosue; Yoshiko Mizuno; Kotaro Nochioka; Masaharu Nakayama; Takamasa Iwai; Yoshihiro Miyamoto; Masanobu Ishii; Taishi Nakamura; Kenichi Tsujita; Hisahiko Sato; Hideo Fujita; Ryozo Nagai; on behalf of the CLIDAS Research Group

doi:10.1253/circj.CJ-22-0653

Abstract

Background: Several studies have reported some sex differences in patients with coronary artery diseases. However, the results regarding long-term outcomes in patients with chronic coronary syndrome (CCS) are inconsistent. Therefore, the present study investigated sex differences in long-term outcomes in patients with CCS after percutaneous coronary intervention (PCI).

Methods and Results: This was a retrospective, multicenter cohort study. We enrolled patients with CCS who underwent PCI between April 2013 and March 2019 using the Clinical Deep Data Accumulation System (CLIDAS) database. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. In all, 5,555 patients with CCS after PCI were included in the analysis (4,354 (78.4%) men, 1,201 (21.6%) women). The median follow-up duration was 917 days (interquartile range 312–1,508 days). The incidence of MACE was not significantly different between the 2 groups (hazard ratio [HR] 1.20; 95% confidential interval [CI] 0.97–1.47; log-rank P=0.087). After performing multivariable Cox regression analyses on 4 different models, there were still no differences in the incidence of MACE between women and men.

Conclusions: There were no significant sex differences in MACE in patients with CCS who underwent PCI and underwent multidisciplinary treatments.

In the modern era, cardiovascular diseases, such as coronary artery disease (CAD), are the primary causes of death in Japan.¹ Several epidemiological and clinical studies have reported that there are differences between women and men with CAD regarding patient background and prognosis. Many studies have shown that short- and long-term prognosis of acute coronary syndrome is worse for women than for men.²^–⁵ This may be because bleeding events⁶^,⁷ and reinfarction⁸ are more common in women than in men, and chest symptoms in women are atypical.⁹ In contrast, the prognoses of stable angina are inconsistent, with some studies reporting no difference between men and women¹⁰^–¹² and others reporting worse prognosis for men¹³^,¹⁴ or for women.¹⁵ We hypothesized that this discrepancy may be primarily caused by differences in confounding factors, definitions of adverse outcomes, and follow-up durations. Hence, we performed a high-quality, multicenter cohort study to demonstrate differences in long-term prognosis between women and men with chronic coronary syndrome (CCS) after percutaneous coronary intervention (PCI) with multiple adjustments.

The aim of the present study was to investigate sex differences in the long-term prognosis of CCS after PCI using a Japanese multicenter database from the Clinical Deep Data Accumulation System (CLIDAS).

Methods

Clinical Deep Data Accumulation System

CLIDAS acquires clinical information, including patient background, laboratory data, prescriptions, echocardiographic parameters, electrocardiograms, cardiac catheterization reports, and long-term prognosis. Presently, 7 hospitals (6 university hospitals and the National Cerebral and Cardiovascular Center Hospital in Japan) are participating in CLIDAS. Standardized Structured Medical Information eXchange version 2 (SS-MIX2) standard storage was used to collect essential patient information, prescriptions, and laboratory data from electronic medical records; SS-MIX2 extended storage was used to collect physiological test results, cardiac catheterization reports, and cardiac catheter intervention reports.¹⁶ CLIDAS was developed as the Japan Ischemic Heart Disease Multimodal Prospective Data Acquisition for Precision Treatment (J-IMPACT) project launched in 2015, which aimed to establish a hospital information system (HIS)-based system to capture medical records and other clinical data electronically for clinical studies in standardized formats.¹⁷ Briefly, data from HIS, a picture archiving and communication system, and a physiology server were linked to a multipurpose clinical data repository system (MCDRS) through the SS-MIX2 standard and extended storage. After anonymization, each facility’s output data were sent through the facility’s own MCDRS server to the CLIDAS server.¹⁷ Data managers and researchers at each facility collected patient background information and follow-up data. Finally, each researcher analyzed the data stored on the CLIDAS server.

Study Design and Clinical Outcomes

This was a retrospective multicenter observational study that included patients with CAD who underwent PCI at 7 hospitals between April 2013 and March 2019.¹⁸ Patients with acute coronary syndrome and those without event data were excluded. The final study population was divided into 2 groups based on sex. This study was approved by the Institutional Review Board of Jichi Medical University Saitama Medical Center (S21-047) and was conducted per the ethical principles of the Declaration of Helsinki. The requirement for written informed consent was waived because of the study’s retrospective design.

The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure. The secondary outcomes were time to cardiovascular death, myocardial infarction, and hospitalization for heart failure. The event-free time was calculated from the index PCI to the event date or the last follow-up date.

Definitions

All baseline laboratory data were calculated as the average values from 60 days before the index PCI to 30 days after the procedure. CCS was defined as cases of PCI other than acute coronary syndrome.¹⁸ The definition of CCS in the present study was almost identical to stable CAD with obstructive epicardial arteries because our database included patients who underwent PCI. Hypertension was defined as a systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or medical treatment for hypertension at index PCI. Diabetes was defined as HbA1c ≥6.5%, casual blood glucose ≥200 mg/dL, fasting blood glucose ≥126 mg/dL, or medical treatment for diabetes at the index PCI. Dyslipidemia was defined as a medical treatment for dyslipidemia at the index PCI or a description of dyslipidemia on electronic medical records. Estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine (Cr) concentration, age, weight, and sex using the following formula:¹⁹

eGFR = 194 × Cr^−1.094 × age^−0.287 (in men)

eGFR = 194 × Cr^−1.094 × age^−0.287 × 0.739 (in women)

For medication status, we counted the number of prescriptions between −10 days before and 10 days after the index PCI.

The number of diseased vessels was defined as the number of coronary arteries with severe stenosis (≥75%) in the major epicardial coronary segments of the right coronary artery, left anterior descending artery, and left circumflex artery, including their branch lesions, that underwent PCI. The diseased left main trunk (LMT), defined as ≥75% stenosis, was counted separately. Patients were classified according to the combination of the number of diseased vessels and LMT disease. We used echocardiographic findings closest to the index PCI, performed between −100 and 0 days before the index PCI. Left ventricular ejection fraction (LVEF) was calculated using the modified Simpson’s rule; however, the Teichholz method was used for LVEF measurement if data of the modified Simpson’s rule were missing.

Statistical Analysis

The Shapiro-Wilk test was used to determine whether continuous variables were normally distributed. Normally distributed continuous variables are expressed as the mean±SD, whereas non-normally distributed continuous variables are expressed as the median with interquartile range (IQR). Normally distributed continuous variables were compared between groups using unpaired Student’s t-test, whereas non-normally distributed continuous variables were compared using the Mann-Whitney U test. Categorical variables are expressed as numbers and percentages and were compared using the Chi-squared or Fisher’s exact test for small samples.

The Kaplan-Meier method was used to estimate survival functions, and statistical differences between groups were compared using log-rank tests. The patients were censored when they were lost to follow-up. Cox regression analyses were conducted to clarify the impact of sex differences on MACE. Age, sex, body mass index, eGFR, left main (LM) disease or 3-vessel disease (3VD), hypertension, diabetes, dyslipidemia, history of myocardial infarction, history of hospitalization for heart failure, history of stroke, history of atrial fibrillation, hemodialysis, and hemoglobin levels at baseline were used as covariates in Model 1. Model 2 was performed using covariates in Model 1 and B-type natriuretic peptide (BNP) values. Model 3 was performed using covariates in Model 2, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, diuretics, statins, and calcium channel blockers at baseline. Model 4 was performed using covariates in Model 3 and LVEF at baseline. Because the number of missing values for LVEF was not small, Model 4 needs to be interpreted with caution. Both BNP and LVEF values were entered into the model as categorical variables (BNP ≥100 pg/mL or not; LVEF ≥50% or not). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. For missing values, a complete case analysis was performed. All reported P values were determined by 2-sided analysis, and P<0.05 was considered statistically significant. P values are presented without adjusting for multiple comparisons in an exploratory manner.

All data were analyzed using SPSS ver. 28 for Windows (SPSS Inc., Chicago, IL, USA).

Results

The CLIDAS database included 9,936 consecutive patients who underwent PCI between April 2013 and March 2019. Of these, 5,555 patients with CCS after PCI were analyzed and divided into 2 groups, namely men (n=4,354; 78.4%) and women (n=1,201; 21.6%). The study flowchart is shown in Figure 1.

Figure 1.

Study flowchart. CLIDAS, Clinical Deep Data Accumulation System; PCI, percutaneous coronary intervention.

Table 1 presents the baseline characteristics of the 2 groups. The median age was higher for women than men (75 [IQR 68–80] vs. 70 [IQR 64–77] years, respectively). The prevalence of chronic kidney disease, a history of hospitalization for heart failure, baseline low-density lipoprotein cholesterol concentrations, and baseline BNP concentrations were higher for women than men. In contrast, the prevalence of diabetes, a history of PCI, a history of myocardial infarction, and baseline hemoglobin were higher for men than women. Prescriptions for diuretics and calcium channel blockers were higher for women than men.

Table 1. Baseline Characteristics in the Study Cohort and in Men and Women Separately

	All (n=5,555)	No. (%) missing data	Men (n=4,354)	Women (n=1,201)	P value
Age (years)	72 [65–78]	0	70 [64–77]	75 [68–80]	<0.001
Height (cm)	163.0 [156.0–168.7]	20 (0.4)	165.0 [161.0–170.0]	150.0 [146.0–154.0]	<0.001
Weight (kg)	63.0 [55.0–71.0]	37 (0.7)	65.0 [59.0–73.0]	52.0 [46.0–59.9]	<0.001
Body mass index (kg/m²)	23.9 [21.7–26.3]	55 (1.0)	24.0 [22.0–26.3]	23.4 [20.8–26.2]	<0.001
Hypertension	4,564 (82.6)	28 (0.5)	3,572 (82.5)	992 (82.8)	0.81
Dyslipidemia	4,323 (78.3)	33 (0.6)	3,396 (78.5)	927 (77.5)	0.46
Diabetes	2,567 (46.6)	42 (0.8)	2,045 (47.4)	522 (43.6)	0.022
Atrial fibrillation	348 (6.3)	28 (0.5)	284 (6.6)	64 (5.3)	0.12
Chronic kidney disease	2,701 (49.7)	116 (2.1)	2,083 (48.9)	618 (52.5)	0.027
Hemodialysis	422 (7.6)	38 (0.7)	347 (8.0)	75 (6.3)	0.046
History of CABG	358 (6.5)	31 (0.6)	291 (6.7)	67 (5.6)	0.16
History of PCI	1,393 (25.2)	33 (0.6)	1,155 (26.7)	238 (19.9)	<0.001
History of MI	903 (16.4)	41 (0.7)	776 (18.0)	127 (10.6)	<0.001
History of hospitalization for HF	470 (8.5)	31 (0.6)	342 (7.9)	128 (10.7)	0.002
History of stroke	631 (11.4)	35 (0.6)	506 (11.7)	125 (10.4)	0.22
SBP on admission (mmHg)	127 [115–140]	86 (1.5)	126 [115–139]	128 [116–142]	0.002
DBP on admission (mmHg)	69 (61–78)	88 (1.6)	70 (61–78)	68 (60–77)	<0.001
Laboratory data
Hemoglobin (g/dL)	12.8 [11.5–13.9]	398 (7.2)	13.1 [11.9–14.1]	11.7 [10.6–12.6]	<0.001
HbA1c (%)	6.2 [5.7–6.8]	257 (4.6)	6.2 [5.7–6.8]	6.1 [5.7–6.8]	0.96
Total cholesterol (mg/dL)	165.0 [144.0–186.0]	126 (2.3)	162.0 [141.5–182.2]	177.0 [153.2–200.0]	<0.001
LDL-C (mg/dL)	88.6 [71.8–107.6]	82 (1.5)	86.9 [70.6–105.0]	95.6 [78.0–118.2]	<0.001
HDL-C (mg/dL)	46.3 [39.0–55.5]	111 (2.0)	45.0 [38.0–53.9]	51.8 [43.2–61.0]	<0.001
Triglyceride (mg/dL)	120.5 [88.0–169.0]	68 (1.2)	122.0 [88.0–172.0]	116.0 [88.0–157.7]	0.006
Creatinine (mg/dL)	0.91 [0.76–1.14]	120 (2.2)	0.94 [0.81–1.18]	0.73 [0.62–0.96]	<0.001
eGFR (mL/min/1.73 m²)	60.2 [46.0–72.5]	120 (2.2)	60.6 [46.8–72.9]	58.7 [42.9–71.3]	0.006
C-reactive protein (mg/dL)	0.23 [0.89–0.75]	440 (7.9)	0.23 [0.09–0.73]	0.23 [0.09–0.81]	0.89
Uric acid (mg/dL)	5.7 [4.8–6.6]	417 (7.5)	5.8 [5.0–6.7]	5.1 [4.2–6.1]	<0.001
BNP (pg/mL)	55 [24–170]	731 (13.2)	51 [22–150]	72 [30–229]	<0.001
Prescriptions^A
Aspirin	5,103 (91.9)	0	4,013 (92.2)	1,090 (90.8)	0.11
Thienopyridine	4,875 (87.8)	0	3,815 (87.6)	1,060 (88.3)	0.55
β-blockers	3,049 (54.9)	0	2,399 (55.1)	650 (54.1)	0.55
ACEI/ARB	3,207 (57.7)	0	2,507 (57.6)	700 (58.3)	0.66
Diuretics	1,264 (22.8)	0	927 (21.3)	337 (28.1)	<0.001
Statins	4,195 (75.5)	0	3,282 (75.4)	913 (76.0)	0.65
Calcium channel blockers	2,519 (45.3)	0	1,900 (43.6)	619 (51.5)	<0.001

Unless indicated otherwise, data are presented as n (%) or the median [interquartile range]. ^APrescriptions from −10 days before to 10 days after the index percutaneous coronary intervention (PCI). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; SBP, systolic blood pressure.

Table 2 presents angiographic and echocardiographic findings for the 2 groups. Right CAD and LM disease were more frequently observed in men than women. Although not significant, LM disease or 3VD tended to be more common in men than women (19.6% vs. 17.9%). Median LVEF was lower in men than in women (61.0% [IQR 48.9–67.6%] vs. 65.7% [57.0–71.7%]). Left ventricular mass and geometry (e.g., left ventricular internal dimension in diastole, left ventricular internal dimension in systole, and left ventricular mass index) were larger in men than in women.

Table 2. Angiographic and Echocardiographic Findings in the Study Cohort and in Men and Women Separately

	All (n=5,555)	No. (%) missing data	Men (n=4,354)	Women (n=1,201)	P value
Angiographic findings
RCA disease	2,617 (51.8)	507 (9.1)	2,093 (52.7)	524 (48.6)	0.017
LM disease	388 (7.7)	507 (9.1)	329 (8.3)	59 (5.5)	0.002
LAD disease	3,642 (72.1)	507 (9.1)	2,866 (72.2)	776 (72.0)	0.89
LCX disease	2,155 (42.7)	507 (9.1)	1,716 (43.2)	439 (40.7)	0.14
1VD	2,701 (53.5)	507 (9.1)	2,160 (54.4)	541 (50.2)	0.014
LM disease or 3VD	973 (19.3)	507 (9.1)	780 (19.6)	193 (17.9)	0.20
Echocardiographic findings^A
LVEF (%)	62.0 [50.0–68.7]	2,620 (47.2)	61.0 [48.9–67.6]	65.7 [57.0–71.7]	<0.001
LVDd (mm)	48.0 [43.9–53.0]	2,861 (51.5)	49.0 [44.9–54.0]	44.4 [40.9–48.4]	<0.001
LVDs (mm)	31.0 [27.0–37.6]	2,311 (41.6)	32.0 [28.0–39.0]	28.0 [24.6–32.9]	<0.001
IVST (mm)	10.0 [9.0–11.4]	2,837 (51.1)	10.0 [9.0–11.5]	10.0 [9.0–11.0]	<0.001
PWT (mm)	10.0 [9.0–11.0]	2,847 (51.3)	10.0 [9.0–11.1]	10.0 [9.0–11.0]	<0.001
LVMI (g/m²)	104.3 [87.3–129.1]	2,900 (52.2)	105.7 [88.2–130.2]	100.0 [83.5–124.9]	<0.001
RWT	0.42 [0.37–0.48]	2,871 (51.7)	0.42 [0.36–0.48]	0.44 [0.38–0.50]	<0.001
Left atrial dimension (mm)	40.0 [35.0–44.0]	3,804 (68.5)	40.0 [35.0–44.0]	38.1 [34.0–43.0]	<0.001

Unless indicated otherwise, data are presented as n (%) or the median [interquartile range]. ^AFrom −100 to 0 days before the index percutaneous coronary intervention. IVST, interventricular septum thickness; LAD, left anterior descending; LCX, left circumflex; LM, left main; LVDd, left ventricular internal dimension in diastole; LVDs, left ventricular internal dimension in systole; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; PWT, posterior left ventricular wall thickness; RCA, right coronary artery; RWT, relative wall thickness; VD, vessel disease.

The median follow-up duration was 917 days (IQR 312–1,508 days). Table 3 presents clinical outcomes in the 2 groups. There were 508 MACE, 149 cardiovascular deaths, 93 myocardial infarctions, and 339 hospitalizations for heart failure. The Kaplan-Meier curves for MACE are shown in Figure 2. The incidence of MACE was not significantly different between the 2 groups (HR 1.20; 95% CI 0.97–1.47; log-rank test, P=0.087). In addition, there was no significant difference in each MACE component between the 2 groups (Figure 3).

Table 3. Clinical Outcomes in the Study Cohort and in Men and Women Separately

	All (n=5,555)	Men (n=4,354)	Women (n=1,201)
MACE	508 (9.1)	389 (8.9)	119 (9.9)
Cardiovascular death	149 (2.7)	112 (2.6)	37 (3.1)
MI	93 (1.7)	73 (1.7)	20 (1.7)
Hospitalization for HF	339 (6.1)	256 (5.9)	83 (6.9)

Data are presented as n (%). MACE, major adverse cardiovascular events. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier curves for major adverse cardiovascular events (MACE) in women and men. P values were calculated using the log-rank test.

Figure 3.

Kaplan-Meier curves for study outcomes in women and men: (A) cardiovascular death; (B) myocardial infarction; and (C) hospitalization for heart failure. P values were calculated using the log-rank test.

Women after menopause are known to have an increased risk of cardiovascular disease and typically develop CAD several years later than men.²⁰ Therefore, we conducted a post hoc stratified analysis for MACE according to age (≥60 or <60 years). The results of the stratified log-rank test did not reach statistical significance (P=0.131).

Cox regression analysis results are presented in Table 4. Compared with men, women were not significantly associated with increased MACE in any of Models 1–4 (Model 1: HR 0.90, 95% CI 0.70–1.15, P=0.40; Model 2: HR 0.86, 95% CI 0.66–1.11, P=0.25; Model 3: HR 0.84, 95% CI 0.65–1.09, P=0.19; Model 4: HR 0.74, 95% CI 0.53–1.04, P=0.087).

Table 4. Cox Regression Analysis Predicting MACE

Composite endpoint: MACE	HR	95% CI	P value
Men	Reference
Unadjusted Women	1.20	0.97–1.47	0.088
Adjusted Women (Model 1)	0.90	0.70–1.15	0.40
Adjusted Women (Model 2)	0.86	0.66–1.11	0.25
Adjusted Women (Model 3)	0.84	0.65–1.09	0.19
Adjusted Women (Model 4)	0.74	0.53–1.04	0.087

The Cox regression analysis was performed using the following covariates: Model 1 was adjusted for age, sex, body mass index, eGFR, LM disease or triple-VD, hypertension, diabetes, dyslipidemia, history of MI, history of hospitalization for HF, history of stroke, history of atrial fibrillation, hemodialysis, and hemoglobin levels at baseline. Model 2 was adjusted for BNP concentrations in addition to covariates in Model 1. Model 3 was adjusted for the use of β-blockers, ACEIs or ARBs, diuretics, statins, and calcium channel blockers at baseline in addition to covariates in Model 2. Model 4 was adjusted for LVEF at baseline in addition to covariates in Model 3. Both BNP and LVEF values were entered into the model as categorical variables (BNP ≥100 pg/mL or not; LVEF ≥50% or not). CI, confidence interval; HR, hazard ratio. Other abbreviations as in Tables 1–3.

Discussion

The present study revealed no significant differences for MACE, defined as a composite of cardiovascular death, non-fatal myocardial infarction, or hospitalization for heart failure, between women and men with CCS after PCI. After multiple adjustments, the results of every model consistently showed no significant differences between women and men. In addition, no differences were found between women and men under and over 60 years of age in the stratified analysis. The recent evidence-based treatments after PCI in patients with CCS may have reduced sex differences.

Although several studies have focused on the relationship between sex differences and prognosis in CAD, our study has the advantage of adjusting for confounding factors in 4 different models and performing stratified analyses. Because there were a few missing values for BNP and echocardiographic data, multivariable analyses were performed on several models; however, the direction of these results was generally consistent. Furthermore, our stratified analysis, which compared the impact of MACE in women and men under and over 60 years of age (the cut-off point given by the World Health Organization for defining an older population²¹), revealed that there were no consistent differences in MACE between women and men. Menopause transition, which is the transition from reproductive to post-reproductive life in women,²² is the leading cause of adverse changes in the risk of cardiovascular diseases.²⁰ In contrast, women in the premenopausal generation have a lower incidence of cardiovascular disease than men.²³ The present cohort of patients with CCS who underwent PCI comprises young women with cardiovascular risk factors beyond the protective effect of estrogen; it is possible that no significant sex difference for MACE was found in patients aged below 60 years.

Several studies have demonstrated in that there are differences in clinical outcomes between women and men. The American College of Cardiology’s National Cardiovascular Data Registry (NCDR) revealed differences in in-hospital mortality by sex and ethnicity in patients with stable angina.¹⁵ In the NCDR results, the rate of in-hospital mortality was higher for White women than White men with stable angina among patients referred for diagnostic coronary angiographic evaluation (n=375,886), with no gender differences noted for other ethnic subsets.¹⁵ Conversely, a Japanese multicenter registry, called the Japan Cardiovascular Database (JCD), demonstrated that there was no difference in in-hospital mortality between women and men, including those with acute coronary syndrome and CCS (n=10,220); however, women had higher rates of complications than men.⁶ The differences in in-hospital mortality results between these 2 studies may be related to differences in the number of cases; however, the NCDR results indicating differences by ethnicity were interesting. In the present study, we examined the Japanese multicenter population and found that unadjusted MACE rates were similar between women and men; similar results were obtained after adjustments. Unlike the NCDR and JCD outcomes, our study evaluated MACE. However, there were no sex differences in the post-PCI patients with CCS. A previous prospective multicenter registry called CLARIFY (Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease) showed that 1-year outcomes, defined as a composite of cardiovascular death, non-fatal myocardial infarction, or stroke, were similar between women and men.¹⁰ That study comprised 33,285 outpatients with stable CAD receiving standard management, including 1,024 Japanese/Korean patients. The CLARIFY registry enrolled outpatients with stable CAD, and the incidence of revascularization in women was lower than that in men.¹⁰ Another prospective multicenter registry in Europe, which enrolled patients with a new presentation of stable angina attending a cardiology service, revealed that women were less likely to undergo exercise electrocardiography and have coronary angiography.²⁴ In addition, women were less likely to be prescribed antiplatelet and statin therapy than men, even after confirming CAD. As in the CLARIFY registry described above, women with confirmed CAD in the European multicenter registry had a lower rate of revascularization than men. However, this European registry revealed that women with proven CAD were twice as likely as men to experience death or non-fatal myocardial infarction during the 1-year follow-up period. In contrast, our study included all patients with stable CAD who were considered to require PCI according to the current guidelines based on symptoms and the extent of ischemia. Generally, it has been suggested that women have fewer typical chest symptoms and a lower cardiovascular risk than men, contributing to the apparent lower prevalence of CAD.²⁵^,²⁶ It is of note that the present study focused on post-PCI patients with CCS; it also used high-quality data without human data entry errors, because the data were extracted directly from each institution’s electronic medical records. An additional strength of this study is that it adjusted for multiple models with more factors affecting MACE than previous studies and found no sex differences for MACE.

A previous cohort study of patients with CCS in western Denmark between 2004 and 2016 revealed that there was a substantial decrease in the risk of adverse cardiovascular events, including myocardial infarction, ischemic stroke, cardiac death, and all-cause death, in both women and men.²⁷ This improved prognosis may reflect advances in stent technology,²⁸ proper evaluation of target lesions,²⁹^–³¹ cardiac rehabilitation programs,³² and optimal medical therapy (OMT). Notably, the results of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial showed that the importance of OMT in patients with CCS has become evident.³³ A previous study demonstrated that a higher rate of OMT after coronary artery bypass grafting (CABG) was associated with a lower 2-year death rate or myocardial infarction.³⁴ Compared with patients taking all drugs prescribed as OMT, there was no significant difference in the 2-year rate of death or myocardial infarction for those taking more than half of the prescribed OMT. In contrast, the 2-year rate of death or myocardial infarction for those taking less than half of the prescribed OMT was 1.69-fold higher.³⁴ The CREDO-Kyoto registry, a Japanese multicenter registry that enrolled patients who underwent their first PCI or CABG between 2000 and 2002, found that only approximately 30% of all patients were prescribed statins at discharge.¹³^,³⁵ The incidence of all-cause death was lower in women than in men after multiple adjustments, although the endpoints and study population were different from those in the present study. In addition, the CREDO-Kyoto registry pooled patients from Cohort 2 (from 2005 to 2007; the era of first-generation drug-eluting stents) and Cohort 3 (from 2011 to 2013; the era of second-generation drug-eluting stents), and found that approximately 65% of all patients were prescribed statins at discharge after PCI.³⁶ In CREDO-Kyoto registry Cohorts 2 and 3, although there were no sex differences in adjusted hospitalization rates for heart failure in the stable CAD stratum, adjusted all-cause mortality was lower in women than in men, as in the CREDO-Kyoto registry from 2000 to 2002.³⁶ Although the present study had different endpoints to those of the CREDO-Kyoto study, we included a more recent population than the two CREDO-Kyoto studies described above, with approximately 75% of all patients being prescribed statins and a median low-density lipoprotein cholesterol level of 88 mg/dL at baseline for all patients, reflecting the results of previous randomized controlled trials on the benefits of high-intensity statins.³⁷^–³⁹ Recent advances in OMT may have contributed to the lack of sex differences in our study.

The present study has some limitations. First, selection bias may have occurred due to the retrospective design. However, we collected consecutive cases from 7 hospitals to reduce the negative effects of selection bias over the study period. Second, owing to missing echocardiographic data and BNP values, it is possible that the results obtained are biased. To address this issue, we used different models in multivariable analyses. Although we took care in interpreting the results of Model 4, which contained many missing LVEF values, each model was oriented in the same direction. Third, the changes in medication dosages during the follow-up period may have affected the clinical outcomes because medication dosages could not be obtained. Future studies should also obtain data on medication dosages. Fourth, the prescribing rate in this study may be lower than the actual prescribing rate because the details of discontinued prescriptions could not be obtained from electrical records. Concerning this, we tried retrieving medications prescribed 10 days before and after the index PCI to obtain as many medications as possible from sources other than discontinued prescriptions. Fifth, the CLIDAS database included unsuccessful PCI cases, which may have influenced the slightly lower rate of antiplatelet medications despite the post-PCI cohort. However, because unsuccessful PCI cases were only a small fraction of the cohort, they are unlikely to have had a significant impact on the study results. Sixth, because our angiographic findings were taken directly from cardiac catheterization reports of each facility, the exact frequency of complete revascularization is insufficiently ascertained, because not all reports described the degree of stenosis for each PCI. Seventh, there are some sex-independent risk factors, including age, hypertension, dyslipidemia, high-risk diet, physical inactivity, and alcohol consumption,²⁵ in this study and, as shown in Table 1, there were baseline differences in these risk factors. Therefore, multivariable Cox regression analysis was performed to adjust for these effects. However, we were unable to acquire information regarding physical activity and alcohol consumption. This limitation is due to the retrospective nature of the study.

Conclusions

There were no significant differences in MACE between women and men among patients with CCS who underwent PCI and received multidisciplinary treatments, including guideline-directed medical therapies.

Acknowledgments

The authors extend their appreciation to Kowa Company Limited for funding the development of CLIDAS. The authors thank all CLIDAS research group members for their contributions. In addition, the authors thank Yuri Matoba (Precision Inc., Tokyo, Japan) for helping us integrate the data.

Sources of Funding

CLIDAS was developed with funding from Kowa Company Limited.

Disclosures

K.K., K.T., and R.N. are members of Circulation Journal’s Editorial Team. T.M. has received research grants from Amgen and honoraria from Abbott Medical and Bayer. T. Kabutoya has received scholarship funds from Abbott Medical. Y.I. has received honoraria from Daiichi Sankyo and Toa Eiyo. K.K. has received research grants and honoraria from Sanwa Kagaku Kenkyusho. A.K. has received honoraria from AstraZeneca, Eli Lilly, and Sumitomo Pharma. K.T. has received research grants from PPD-Shin Nippon Biomedical Laboratories and Alexion Pharmaceuticals; scholarship funds from Abbott Medical, Bayer, Boehringer Ingelheim, Daiichi Sankyo, ITI, Ono Pharmaceutical, Otsuka Pharmaceutical, and Takeda Pharmaceutical; and honoraria from Abbott Medical, Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Medtronic, Kowa, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, and Janssen Pharmaceutical; and is affiliated with the endowed department from Abbott Medical, Boston Scientific, Cardinal Health, Fides-ONE, Fukuda Denshi, GM Medical, ITI, Japan Lifeline, Kaneka Medix, Medical Appliance, Medtronic, Nipro, and Terumo. H.S. reports stock or stock options in Precision. H.F. has received consulting fees from Mehergen Group Holdings and honoraria from Novartis Pharma and Otsuka Pharmaceutical. R.N. has received honoraria from Kowa, Takeda Pharmaceutical, Tanabe-Mitsubishi Pharmaceutical, and Boehringer-Ingelheim. All other authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Institutional Review Board of Jichi Medical University Saitama Medical Center (S21-047).

Data Availability

The deidentified participant data will not be shared.

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