1. INTRODUCTION

It is generally accepted that women have fewer cardiovascular diseases (CVDs) than men.1 According to a literature review, women have less occurrence of fatal coronary heart disease (<1% vs 3.6%) and nonfatal MI (18.3% vs 37.5%) than men.2 This could be caused by gender differences in the pathogenesis of coronary artery diseases (CADs), including the pathological plaque mechanism,3 vascular anatomy, hormonal profiles, coagulation,4 vascular risk factors, lifestyle factors, and socioeconomic status. However, not all clinical observations support that females have favorable clinical outcomes, and the situation is quite different when women already have a preexisting cardiovascular disease.5–9

Recent studies found that women with a history of CVD had poorer clinical outcomes than men.10–13 For example, women had higher 30-day mortality rates after ST-segment elevation myocardial infarction (STEMI),10 as well as a higher risk of developing future acute limb ischemia when suffering from symptomatic peripheral artery disease (PAOD).11 Furthermore, after stroke, women have a higher risk of mortality,14 stroke-related disability, and poorer quality of life than men.15 All of this evidence shows that if women have CVD, the long-term outcome is unfavorable.

Recently, advances in percutaneous coronary intervention (PCI) and intracoronary imaging have greatly improved clinical outcomes. However, there is limited information about the long-term outcome in different sexes after coronary intervention. Kosmidou et al13 reported that women have a higher risk of major adverse cardiovascular events (MACE) and target lesion failure than men at 5 years after PCI. In that study, women had a higher risk of cardiac death, myocardial infarction (MI), and ischemia-driven revascularization following PCI. Women who received PCI usually exhibit more comorbidities than a man such as older, hypertensive, and/or diabetic that may cause an adverse outcomes.16 However, there is little information on other important outcomes, such as congestive heart failure and stroke in women.

In addition, women aged <55 years old seem to have higher risk. Another study reported a higher risk in women aged <60 years old after acute myocardial infraction, but not in women aged >60 years old.10 This suggests that relatively young women with CAD have worse outcomes. Therefore, this study investigates the impact of sex differences in long-term outcomes following PCI among various age groups and extends observed endpoints to stroke and congestive heart failure.

2. METHODS 2.1. Baseline data collection

The design and results from our larger, retrospective, single-center observational study has been published previously.17,18 Briefly, our study examined patients with symptomatic CAD who were successfully treated with PCI. The diagnosis of CAD included (1) positive evidence of ischemic changes such as treadmill test and nuclear stress test results, (2) a history of angina with an ischemic change in ECG recordings, and (3) MI attack or angina symptoms with a significant stenosis lesion in coronary computed tomography angiography. Between July 2006 and December 2015, there were 6447 eligible subjects received PCI with either coronary stenting or balloon angioplasty at Taipei Veteran General Hospital, Taiwan.

Patients included in the analysis were categorized according to sex and age categories. They were subdivided into three groups: those with aged <60 years; those aged 60–74 years; and those aged >75 years according to definitions of elderly people.19 A well-trained nurse research staff gathered baseline characteristics and risk factors from electronic medical records, including age, sex, smoking habit, family history of premature CAD, history of hypertension, diabetes, hyperlipidemia, and cerebral vascular disease. The baseline urine acid levels, lipid profiles, sugar measurements, and medications after PCI were collected in this study.

2.2. Ethics approval and consent to participate

All procedures were conducted in accordance with the Declaration of Helsinki and were approved by the Ethics Committee and Independent Review Board of Taipei Veterans General Hospital as well as the Joint IRB Ethics Committee Review Board in Taiwan. All patients should give their written informed consent before enrollment.

2.3. Clinical follow-up for adverse cardiovascular events

The primary outcome was MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal stroke). The secondary outcome was the total major cardiovascular events, which was a composite of MACE plus hospitalization for congestive heart failure (MACE + CHF). Heart failure was diagnosed in our registry according medical record and ICD-10. MI was confirmed in patients presenting with ischemic symptoms with elevated serum cardiac enzyme levels and/or characteristic ECG changes. Ischemic stroke was confirmed as an obstruction within a brain blood vessel with imaging evidence by either MRI or CT scan and a new neurological deficit lasting for at least 24 hours. The protocol for follow-up of cardiovascular (CV) events was similar to previous reports.17,18

2.4. Statistics

Continuous variables were expressed as the mean and standard deviation in the presence of a normal distribution. Categorical variables were presented as both absolute frequencies (number of patients) and relative frequencies (percentage). The categorical variables were analyzed by a one-way analysis of variance (ANOVA), while subgroup comparisons of categorical variables were assessed by a χ2 test or Fisher’s exact test.

The primary and secondary outcomes were presented as overall percentages and expressed as proportions with a 95% confidence interval (CI). The event-free survival rate between different groups was calculated using the Kaplan–Meier method with significance evaluation using log rank tests. Hazard ratios (HRs) from a Cox regression model were used to analyze the outcome. P values of <0.05 were considered significant.

In addition to crude HRs, adjusted HRs were estimated after adjustment for potential confounding factors, including hypertension, diabetes, smoking habit, and revascularization. Statistical analysis was performed using SPSS software (Version 22.0, SPSS Inc., Chicago, IL, USA) and R version 3.2.3 (http://www.R-project.org/; R Foundation for Statistical Computing, Vienna, Austria). In all of the tests, the two-tailed alpha level for significance was 0.05.

3. RESULTS

From 2005 to 2015, a total of 6447 CAD patients, including 4833 males and 1614 females who underwent successful coronary intervention, were respectively enrolled in this study. The baseline characteristics of the participants are presented in Table 1. The median age of the male patients was 68 years, and that of the female was 70 years. Males had more acute coronary syndromes at enrollment (40.6% vs 36.1%, p = 0.001) and smokers (40.8% vs 6.6%, p < 0.0001). Females had more comorbidities than males, including hypertension (89.1% vs 85.7%, p = 0.001), diabetes (51.1% vs 35.1%, p < 0.0001), PAOD (7.3% vs 4.4%, p < 0.0001), and hyperlipidemia (45.5% vs 41.6%, p = 0.007).

Table 1 - Baseline characteristics of the study population by sex (n = 6447) Male (n = 4833) Female (n = 1614) p Age, y 68.19 ± 13.73 70.83 ± 10.63 <0.0001 Body mass index, kg/m2 25.57 ± 4.16 25.38 ± 4.48 0.167 Systolic blood pressure, mmHg 129.43 ± 19.7 134.14 ± 21.4 <0.0001 Diastolic blood pressure, mmHg 73.86 ± 12.11 72.37 ± 12.3 <0.0001 Chronic disease  Hypertension, n (%) 4140 (85.66%) 1438 (89.10%) 0.001  Diabetes mellitus, n (%) 1697 (35.11%) 824 (51.05%) <0.0001  Acute coronary syndrome, n (%) 1964 (40.64%) 582 (36.06%) 0.001  Stroke, n (%) 262 (5.42%) 107 (6.63%) 0.070  PAOD, n (%) 211 (4.37%) 118 (7.31%) <0.0001  Hyperlipidemia, n (%) 2011 (41.61%) 734 (45.48%) 0.007  Smoking, n (%) 1970 (40.76%) 107 (6.63%) <0.0001 Uric acid, mg/dL 6.55 ± 1.85 6.21 ± 2.02 <0.0001 Total cholesterol, mg/dL 169.6 ± 39.45 180.6 ± 44.98 <0.0001  Triglyceride, mg/dL 133.73 ± 85.24 147.78 ± 87.08 <0.0001  HDL-C, mg/dL 41.57 ± 11.27 45.65 ± 13.6 <0.0001  LDL-C, mg/dL 105.24 ± 33.85 106.64 ± 37.15 0.207 Glucose, mg/dL 118.78 ± 39.8 132.75 ± 49.9 <0.0001 HbA1C,% 6.93 ± 1.36 7.29 ± 1.43 <0.001 Serum creatinine, mg/dL 1.52 ± 1.6 1.72 ± 1.99 <0.0001 eGFR, mL/min/1.73m2 64.87 ± 25.95 55.07 ± 30.36 <0.0001 CAD severity  SVD, n (%) 1373 (28.43%) 509 (32.01%) 0.02  DVD, n (%) 1541 (31.90%) 494 (31.07%)  TVD, n (%) 1916 (39.67%) 587 (36.92%) Stent characteristics  DES stent, n (%) 2569 (53.16%) 995 (61.65%) <0.0001  BMS stent, n (%) 1634 (33.81%) 458 (28.38%) <0.0001 Medications  ACEI, n (%) 1033 (21.37%) 227 (14.06%) <0.0001  ARB, n (%) 1583 (32.75%) 639 (39.59%) <0.0001  Beta blocker, n (%) 2092 (43.29%) 778 (48.20%) 0.001  Calcium channel blocker, n (%) 1463 (30.27%) 619 (38.35%) <0.0001  Statins, n (%) 2559 (52.95%) 865 (53.59%) 0.653  Diuretics Thiazide, n (%) 444 (9.19%) 187 (11.59%) 0.005

Values are n (%) or mean ± SD.

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; BMS = bare metal stent; CAD = coronary artery disease; DES = drug eluting stent; DVD = double vessel disease; HDL = high-density lipoprotein; LDL = low density lipoprotein; PAOD = peripheral arterial occlusive disease; SVD = single vessel disease; TVD = triple vessel disease.

In addition, males had a higher percentage of triple vessel disease (39.67% vs 36.9%). Both sexes had similar numbers of stent implantations, but slightly more female use drug-applied stents than male. Females also took more medicines than males at baseline, including ACEI/ARB (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers), beta-blockers, and calcium channel blockers.

Table 2 shows the baseline characteristics of study subjects according to age group. Young patients seemed to have higher BMI, more hyperlipidemia disease, and more frequent smoking habits. Females tended to have worse lipid profiles compared with males in the same age categories. Younger patients of both sexes had less multivessel disease and a higher rate of taking medications except for thiazide diuretics. Both males and females had well-controlled lipid profiles and blood sugar.

Table 2 - Baseline characteristics of the study population in the different sex and age categories Male Female p <60 60–75 >75 <60 60–75 >75 (n = 1490) (n = 1359) (n = 1984) (n = 234) (n = 778) (n = 602) Body mass index, kg/m2 27.1 ± 4.8 25.7 ± 3.6 24.3 ± 3.5 26.4 ± 5.5 25.5 ± 4.4 24.8 ± 4.1 <0.0001 Systolic blood pressure, mmHg 127.3 ± 18.6 129.1 ± 18.7 131.3 ± 21.0 130.9 ± 21.6 135.0 ± 20.8 134.2 ± 22.1 <0.0001 Diastolic blood pressure, mmHg 78.4 ± 11.8 74.6 ± 11.5 69.9 ± 11.4 77.1 ± 12.3 73.0 ± 11.39 69.6 ± 12.8 <0.0001 Chronic disease  Hypertension, n (%) 1259 (84.5) 1169 (86.02) 1712 (86.29) 200 (85.47) 713 (91.65) 525 (87.21) 0.0003  Diabetes mellitus, n (%) 464 (31.14) 546 (40.18) 687 (34.63) 112 (47.86) 416 (53.47) 296 (49.17) <0.0001  Acute coronary syndrome, n (%) 663 (44.5%) 512 (37.7) 789 (39.7) 88 (37.6) 234 (30.1) 260 (43.2) <0.0001  Stroke, n (%) 37 (2.48) 68 (5) 157 (7.91) 11 (4.7) 44 (5.66) 52 (8.64) <0.0001  PAOD, n (%) 23 (1.54) 56 (4.12) 132 (6.65) 11 (4.7) 43 (5.53) 64 (10.63) <0.0001  Hyperlipidemia, n (%) 749 (50.27) 582 (42.83) 680 (34.27) 121 (51.71) 375 (48.2) 238 (39.53) <0.0001 Smoking, n (%) 666 (44.7) 543 (39.96) 761 (38.36) 26 (11.11)47 43 (5.53) 38 (6.31) <0.0001 Uric acid, mg/dL 6.5 ± 1.7 6.4 ± 1.8 6.7 ± 2.0 6.1 ± 2.0 6.1 ± 1.9 6.5 ± 2.2 <0.0001 Total cholesterol, mg/dL 178.4 ± 44.6 169.5 ± 38.8 163.2 ± 38.8 193.0 ± 49.0 182.3 ± 47.0 173.1 ± 38.7 <0.0001 Triglyceride, mg/dL 161.7 ± 98.0 134.7 ± 83.4 112.7 ± 69.0 167.1 ± 98.6 152.0 ± 89.2 134.1 ± 76.6 <0.0001 HDL-C, mg/dL 39.5 ± 10.1 41.3 ± 10.9 43.2 ± 12.1 46.1 ± 13.6 46.1 ± 13.5 44.9 ± 13.8 <0.0001 LDL-C, mg/dL 112.7 ± 36.9 104.0 ± 34.4 100.6 ± 30.0 116.3 ± 40.4 108.0 ± 38.3 100.8 ± 33.0 <0.0001 Glucose, mg/dL 120.9 ± 43.6 119.3 ± 39.4 117.1 ± 37.4 139.9 ± 60.3 132.0 ± 48.6 130.6 ± 46.4 <0.0001 eGFR, mL/min/1.73m2 76.6 ± 25.2 65.3 ± 25.6 55.9 ± 23.1 69.7 ± 41.8 56.8 ± 28.8 47.1 ± 23.95 <0.0001 HbA1C, % 7.1 ± 1.5 6.9 ± 1.3 6.8 ± 1.2 7.5 ± 1.7 7.4 ± 1.5 7.0 ± 1.3 <0.0001 Serum creatinine, mg/dL 1.4 ± 1.6 1.6 ± 1.6 1.7 ± 1.3 1.7 ± 2.2 1.7 ± 1.9 1.8 ± 1.6 <0.0001 eGFR, mL/min/1.73m2 76.6 ± 25.2 65.3 ± 25.6 55.9 ± 23.1 69.7 ± 41.8 56.8 ± 28.8 47.1 ± 23.95 <0.0001 CAD   SVD, n (%) 532 (35.7) 368 (27.08) 473 (23.84) 93 (39.74) 253 (35.52) 163 (27.08) <0.0001   DVD, n (%) 495 (33.22) 432 (31.79) 614 (30.95) 71 (30.34) 249 (32.01) 174 (28.9) 0.4826   TVD, n (%) 460 (30.87) 559 (41.1) 897 (45.21) 68 (29.06) 263 (33.8) 256 (42.52) <0.0001 Stent characteristics DES Stent, n (%) 880 (59.06) 814 (59.9) 875 (44.1) 140 (59.83) 483 (62.08) 372 (61.79) <0.0001 BMS Stent, n (%) 422 (28.32) 391 (28.77) 821 (41.38) 63 (26.92) 201 (25.84)A 194 (32.23) <0.0001 Medications ACEI, n (%) 426 (28.59) 276 (20.31) 331 (16.68) 39 (16.67) 105 (13.5) 83 (13.79) <0.0001 ARB, n (%) 431 (28.93) 483 (35.54) 669 (33.72) 85 (36.32) 315 (40.49) 239 (39.7) <0.0001 Beta blocker, n (%) 773 (51.88) 604 (44.44) 715 (36.04) 135 (57.69) 379 (48.71) 264 (43.85) <0.0001 Calcium channel blocker, n (%) 356 (23.89) 415 (30.54) 692 (34.88) 82 (35.04) 321 (41.26) 216 (35.88) <0.0001 Statins, n (%) 987 (66.24) 736 (54.16) 836 (42.14) 140 (59.83) 424 (54.5) 301 (50) <0.0001 Diuretics, n (%) 73 (4.9) 114 (8.39) 257 (12.95) 21 (8.97) 86 (11.05) 80 (13.29) <0.0001

Values are n (%) or mean ± SD.

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; BMS = bare metal stent; CAD = coronary artery disease; DES = drug eluting stent; DVD = double vessel disease; HDL = high-density lipoprotein; LDL = low density lipoprotein; PAOD = peripheral arterial occlusive disease; SVD = single vessel disease; TVD = triple vessel disease.

After a mean period of 52.7 months of follow-up, 614 MACE cases were recorded, including 308 MIs, 120 ischemic strokes, and 224 cardiac deaths. In addition, 510 heart-failure hospitalizations and 1023 total CV events were identified (Table 3). Fig. 1 shows the Kaplan–Meier analysis survival results. Females were significantly associated with a higher risk of cardiac death (Fig. 1B), heart-failure hospitalization (Fig. 1D), MACE (Fig. 1E), and total CV events (Fig. 1F). After adjusting for comorbidities and revascularization procedures, women were associated with a significantly increased risk of cardiac death (HR, 1.78; 95% CI, 1.32-2.41; p < 0.001), Hospitalization for congestive heart failure (HR, 1.53; 95% CI, 1.23-1.89; p < 0.001), MACE (HR, 1.34; 95% CI, 1.10-1.63; p = 0.003), and total CV events (HR, 1.39; 95% CI, 1.20-1.62; p < 0.001) (Table 3).

Table 3 - Clinical outcome in study population according to sex categories Male Female Model 1 Model 2 Model 3 n (%) Event Rate
/100 Pt-Yrs n (%) Event Rate
/100 Pt-Yrs HR 95%CI p HR 95%CI p HR 95%CI p MI 235 (4.86%) 1.12 73 (4.52%) 1.18 1.04 (0.80–1.35) 0.778 1.26 (0.95–1.68) 0.114 1.24 (0.93–1.65) 0.139 Stroke 92 (1.90%) 0.43 28 (1.73%) 0.44 1.04 (0.68–1.59) 0.847 1.06 (0.67–1.67) 0.798 1.05 (0.67–1.64) 0.845 Cardiac death 146 (3.02%) 0.68 78 (4.83%) 1.23 1.68 (1.28–2.21) 0.000 1.84 (1.36–2.48) 0.000 1.78 (1.32–2.41) <0.001 HF 370 (7.66%) 1.79 140 (8.67%) 2.33 1.26 (1.04–1.54) 0.018 1.51 (1.22–1.88) 0.000 1.53 (1.23–1.89) <0.001 Revascularization 977 (20.22%) 5.42 228 (14.13%) 4.03 0.73 (0.64-0.85) <0.001 0.77 (0.66-0.90) 0.001 0.98 (0.84-1.15) 0.816 MACE 450 (9.31%) 2.17 164 (10.16%) 2.67 1.20 (1.00–1.43) 0.051 1.37 (1.13–1.67) 0.002 1.34 (1.10–1.63) 0.003 Total CV event 748 (15.48%) 3.75 275 (17.04%) 4.75 1.22 (1.07–1.41) 0.004 1.42 (1.22–1.65) 0.000 1.39 (1.20–1.62) <0.001

MI = nonfatal myocardial infarction; Stroke = nonfatal stroke; HF = Hospitalization for congestive heart failure.

MACE includes nonfatal MI, nonfatal stoke and cardiac death.

Total CV events includes MACE plus hospitalization for CHF.

The hazard ratio is for the female as compare with the male.

Model 1: Crude hazard ratio.

Model 2: adjusted with history of hypertension, diabetes, smoke.

Model 3: adjusted with history of hypertension, diabetes, smoke, and revascularization.

CHF = congestive heart failure; CV = cardiovascular; MI = nonfatal myocardial infarction; MACE = major cardiovascular events.