Abstract
Background: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD).
Methods and Results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69–0.82, P<0.001, and HR: 0.92, 95% CI: 0.84–1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002).
Conclusions: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.
Sex difference in mortality risk has been discussed for several decades for patients with coronary artery disease (CAD), and several studies suggest the mortality risk is higher in women compared with men among patients with acute myocardial infarction even after adjusting confounders.1–7 However, the sex gap in patients with acute coronary syndrome (ACS) is still disputed. Women are often undertreated as represented by delays to reperfusion, lower prevalence of angiography and revascularization, and a lower rate of guideline-recommended medication therapy.8–16 Therefore, the observed sex gap in mortality risk in ACS might largely be explained by more advanced age, and greater burden of comorbidities of women than in men, once appropriate treatments are implemented in women as in men. Moreover, only a few studies have evaluated sex differences in mortality risk in patients with stable CAD,17–19 and furthermore, there is a scarcity of data evaluating sex differences on broad clinical outcome measures such as heart failure (HF) hospitalization, recurrent myocardial infarction, stroke, and bleeding.1,8,13 Therefore, the aim of this study was to evaluate sex differences in long-term clinical outcomes in patients who underwent first coronary revascularization with percutaneous coronary intervention (PCI) stratified by clinical presentation (ACS or stable CAD) in a large Japanese pooled database.
Methods
Study Population
The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/coronary artery bypass grafting (CABG) Registry Cohort-2 and Cohort-3 are a series of physician-initiated, non-company sponsored, multicenter registries enrolling consecutive patients undergoing first coronary revascularization, either PCI or isolated CABG. Cohort-2 enrolled patients between January 2005 and December 2007 among 26 centers in Japan after approval of first-generation drug-eluting stents (DES) in 2004.20,21 Cohort-3 enrolled patients between January 2011 and December 2013 among 22 centers in Japan after approval of new-generation DES in 2010 (Supplementary Appendix A).22,23
We pooled the patients enrolled in the 2 registries (Cohort-2: n=15,330, and Cohort-3: n=14,927) for a total of 30,257 consecutive patients who underwent first coronary revascularization with PCI or isolated CABG. After excluding 159 patients who refused to participate in the study (Cohort-2: n=99, and Cohort-3: n=60) and 3,782 patients who underwent CABG (Cohort-2: n=2,173, and Cohort-3: n=1,609), we retrieved data for 26,316 patients for the current analysis and divided them according to the clinical presentation (ACS: n=11,119, and stable CAD: n=15,197). There were 2,922 women and 8,127 men in the ACS stratum, and 4,266 women and 10,931 men in the stable CAD stratum (Figure 1).
The study protocols were approved by the relevant institutional review boards at all participating hospitals. As described previously, written informed consent was waived for both registries because of the retrospective nature of the study. However, we excluded patients who refused to participate in the study when contacted at follow-up.24
Definitions and Clinical Outcome Measures
ACS consisted of ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation ACS (NSTEACS). Definitions of STEMI and NSTEACS were described in detail previously.24,25 Patients with CAD other than ACS were considered having stable CAD. Experienced clinical research coordinators from an independent clinical research organization (Research Institute for Production Development, Kyoto, Japan; Supplementary Appendix B) collected the data on baseline clinical, angiographic and procedural characteristics from hospital charts or databases according to the prespecified definitions that were consistent in Cohort-2 and Cohort-3.
The primary outcome measure in this study was all-cause death. The secondary outcome measures were cardiovascular death, noncardiovascular death, MI, definite stent thrombosis, stroke, hospitalization for HF, major bleeding, any coronary revascularization, and target vessel revascularization. The definitions for clinical events were also identical in Cohort-2 and Cohort-3. Definitions of baseline characteristics and clinical outcome measures are described in Supplementary Appendix C. Clinical outcomes such as death, MI, stroke, and major bleeding were adjudicated by the clinical event committee (Supplementary Appendix D).
Data Collection and Follow-up
The clinical research coordinators collected follow-up information by reviewing hospital charts, and additional follow-up information was collected through contact with patients, relatives and/or referring physicians by mail with questions regarding vital status, subsequent hospitalizations, and status of antiplatelet therapy. Median follow-up duration was 5.1 years (interquartile range [IQR]: 4.2–5.9), and the follow-up rate was 98.6% at 1 year, 96.5% at 3 years, and 69.4% at 5 years in Cohort-2. In Cohort-3, median follow-up duration was 5.7 years (IQR: 4.4–6.7), and follow-up rate was 97.5% at 1 year, 94.7% at 3 years, and 82.9% at 5 years.
Statistical Analysis
Continuous variables are expressed as mean±standard deviation or median with IQR. We used Student’s t-test or the Wilcoxon rank sum test based on their distributions to compare continuous variables. Categorical variables sre expressed as frequencies and percentages and were compared using the χ2
test. We estimated cumulative incidence by the Kaplan-Meier method and assessed differences using the log-rank test. To estimate the adjusted hazard ratios (HR) and their 95% confidence intervals (CIs) of women relative to men for the clinical outcome measures, we constructed multivariable Cox proportional hazard models for the entire follow-up period. In these models, we incorporated the 25 clinically relevant risk-adjusting variables according to our previous reports as listed in Table 1.22,23 Continuous risk-adjusting variables other than age were dichotomized according to clinically meaningful reference values to make the proportional hazard assumptions robust and consistent with previous reports.20,26 Because of the large age difference between the women and men, we incorporated age as a continuous variable in the multivariable Cox models. Proportional hazard assumptions for the risk-adjusting variables were assessed on the plots of log (time) vs. log [-log (survival)] stratified by the variable. The assumptions were verified to be acceptable for all the variables.
Table 1. Baseline Characteristics of Patients With ACS or Stable CAD: Women vs. Men
| |
ACS |
P value |
Stable CAD |
P value |
Women
(n=2,992) |
Men
(n=8,127) |
Women
(n=4,266) |
Men
(n=10,931) |
| (A) Clinical characteristics |
| ACS |
|
|
0.65 |
– |
– |
– |
| STEMI |
2,177 (73%) |
5,948 (73%) |
|
– |
– |
– |
| NSTEACS |
815 (27%) |
2,179 (27%) |
|
– |
– |
– |
| Age (years)*,† |
74.8±10.9 |
65.9±11.9 |
<0.001 |
72.7±9.2 |
67.9±10.4 |
<0.001 |
| ≥75 years |
1,652 (55%) |
2,075 (26%) |
<0.001 |
1,961 (46%) |
3,065 (28%) |
<0.001 |
| BMI (kg/m2)*,† |
22.8±3.7 |
23.9±3.5 |
<0.001 |
23.6±4.0 |
24.0±3.4 |
<0.001 |
| <25.0 kg/m2 |
2,262 (76%) |
5,545 (68%) |
<0.001 |
2,938 (69%) |
7,111 (65%) |
<0.001 |
| Hypertension*,† |
2,427 (81%) |
6,395 (79%) |
0.005 |
3,712 (87%) |
9,070 (83%) |
<0.001 |
| Diabetes mellitus*,† |
974 (33%) |
2,771 (34%) |
0.13 |
1,768 (41%) |
4,427 (41%) |
0.30 |
| On insulin therapy |
178 (5.9%) |
365 (4.5%) |
0.002 |
533 (13%) |
1,008 (9.2%) |
<0.001 |
| Current smoking*,† |
422 (14%) |
3,810 (47%) |
<0.001 |
391 (9.2%) |
3,198 (29%) |
<0.001 |
| Heart failure*,† |
1,068 (36%) |
2,153 (27%) |
<0.001 |
844 (20%) |
1,664 (15%) |
<0.001 |
| At admission |
1,041 (35%) |
2,121 (26%) |
<0.001 |
700 (16%) |
1,295 (12%) |
<0.001 |
| Prior heart failure |
106 (3.5%) |
107 (1.3%) |
<0.001 |
261 (6.1%) |
620 (5.7%) |
0.31 |
| LVEF (%) |
55.5±13.2 |
54.6±12.5 |
0.002 |
63.0±12.7 |
60.4±12.7 |
<0.001 |
| ≤40% |
342 (14%) |
859 (13%) |
0.049 |
271 (7.3%) |
801 (8.4%) |
0.03 |
| Prior MI*,† |
108 (3.6%) |
262 (3.2%) |
0.34 |
603 (14%) |
1,857 (17%) |
<0.001 |
| Prior stroke (symptomatic)*,† |
354 (12%) |
792 (9.7%) |
0.002 |
505 (12%) |
1,432 (13%) |
0.04 |
| Peripheral vascular disease*,† |
95 (3.2%) |
273 (3.4%) |
0.67 |
345 (8.1%) |
1,460 (13%) |
<0.001 |
eGFR <30 mL/min/1.73 m2, without
hemodialysis*,† |
262 (8.8%) |
315 (3.9%) |
<0.001 |
207 (4.9%) |
330 (3.0%) |
<0.001 |
| Hemodialysis*,† |
82 (2.7%) |
156 (1.9%) |
0.01 |
221 (5.2%) |
615 (5.6%) |
0.30 |
| eGFR <30 mL/min/1.73 m2 or hemodialysis |
344 (12%) |
471 (5.8%) |
<0.001 |
428 (10%) |
945 (8.6%) |
0.008 |
| Atrial fibrillation*,† |
338 (11%) |
656 (8.1%) |
<0.001 |
350 (8.2%) |
1,056 (9.7%) |
0.006 |
| Hemoglobin (g/dL) |
12.2±1.9 |
14.2±2.0 |
<0.001 |
12.2±1.6 |
13.5±1.9 |
<0.001 |
Thrombocytopenia (platelets
<100×109/L)*,† |
57 (1.9%) |
153 (1.9%) |
1.00 |
49 (1.1%) |
198 (1.8%) |
0.005 |
| COPD*,† |
90 (3.0%) |
302 (3.7%) |
0.08 |
140 (3.3%) |
460 (4.2%) |
0.01 |
| Liver cirrhosis |
68 (2.3%) |
184 (2.3%) |
1.00 |
98 (2.3%) |
320 (2.9%) |
0.04 |
| Malignancy*,† |
314 (11%) |
717 (8.8%) |
0.008 |
432 (10%) |
1,399 (13%) |
<0.001 |
| (B) Procedural characteristics |
| No. of target lesions |
1.4±0.8 |
1.4±0.8 |
0.31 |
1.5±0.8 |
1.5±0.8 |
0.37 |
| Target of LAD |
1,756 (59%) |
4,831 (59%) |
0.49 |
2,776 (65%) |
6,838 (63%) |
0.004 |
| Target of proximal LAD*,† |
1,638 (55%) |
4,599 (57%) |
0.09 |
2,680 (63%) |
6,551 (60%) |
0.001 |
| Target of LCX |
704 (24%) |
2039 (25%) |
0.10 |
1,232 (29%) |
3,205 (29%) |
0.61 |
| Target of RCA |
1,313 (44%) |
3,526 (43%) |
0.65 |
1,629 (38%) |
4,348 (40%) |
0.07 |
| Target of LMCA*,† |
108 (3.6%) |
354 (4.4%) |
0.09 |
158 (3.7%) |
449 (4.1%) |
0.27 |
| Target of CTO*,† |
120 (4.0%) |
370 (4.6%) |
0.24 |
516 (12%) |
1,845 (17%) |
<0.001 |
| Multivessel disease*,† |
1,623 (54%) |
4,265 (53%) |
0.10 |
2,471 (58%) |
6,239 (57%) |
0.35 |
| Radial approach*,† |
482 (16%) |
1,478 (18%) |
0.01 |
1,610 (38%) |
4,879 (45%) |
<0.001 |
| Femoral approach |
2,307 (78%) |
6,157 (76%) |
0.14 |
1,984 (47%) |
4,673 (43%) |
<0.001 |
| IVUS use |
1,385 (46%) |
4,095 (50%) |
<0.001 |
2,660 (62%) |
6,991 (64%) |
0.07 |
| Staged PCI |
618 (21%) |
1,911 (24%) |
0.002 |
813 (19%) |
2,025 (19%) |
0.46 |
| Stent use |
2,718 (91%) |
7,614 (94%) |
<0.001 |
4,070 (95%) |
10,469 (96%) |
0.34 |
| Stent type |
|
|
0.06 |
|
|
0.36 |
| Bare metal |
1,266 (47%) |
3,708 (49%) |
|
757 (19%) |
2,018 (19%) |
|
| Drug-eluting |
1,452 (53%) |
3,906 (51%) |
|
3,313 (81%) |
8,451 (81%) |
|
| Total no. of stents |
1.7±1.3 |
1.7±1.2 |
0.83 |
1.9±1.3 |
2.0±1.4 |
0.02 |
| Total stent length (mm) |
36±29 |
36±29 |
0.42 |
41±31 |
43±34 |
<0.001 |
| Minimum stent diameter (mm) |
2.7±0.7 |
2.9±0.7 |
<0.001 |
2.7±0.5 |
2.8±0.6 |
<0.001 |
| (C) Baseline medications |
| Antiplatelet therapy |
| Thienopyridine |
2,836 (95%) |
7,888 (97%) |
<0.001 |
4,213 (99%) |
10,791 (99%) |
0.91 |
| Ticlopidine |
1,359 (48%) |
3,626 (46%) |
0.10 |
1,920 (46%) |
4,893 (46%) |
0.80 |
| Clopidogrel |
1,457 (49%) |
4,184 (52%) |
0.01 |
2,279 (53%) |
5,866 (54%) |
0.80 |
| Aspirin |
2,928 (98%) |
8,016 (99%) |
0.005 |
4,216 (99%) |
10,816 (99%) |
0.58 |
| Cilostazol |
510 (17%) |
1,440 (18%) |
0.42 |
243 (5.7%) |
676 (6.2%) |
0.27 |
| Statins* |
1,943 (65%) |
5,565 (69%) |
<0.001 |
2,829 (66%) |
6,625 (61%) |
<0.001 |
| β-blockers* |
1,203 (40%) |
3,708 (46%) |
<0.001 |
1,201 (28%) |
3,066 (28%) |
0.91 |
| ACE inhibitor/ARB* |
2,045 (68%) |
5,946 (73%) |
<0.001 |
2,348 (55%) |
5,804 (53%) |
0.03 |
| Nitrates |
782 (26%) |
1,969 (24%) |
0.04 |
1,298 (30%) |
3,162 (29%) |
0.07 |
| Calcium-channel blocker* |
775 (26%) |
1,879 (23%) |
0.002 |
2,330 (55%) |
5,483 (50%) |
<0.001 |
| Nicorandil |
660 (22%) |
1,926 (24%) |
0.07 |
803 (19%) |
1,957 (18%) |
0.19 |
| Oral anticoagulant |
326 (11%) |
854 (11%) |
0.58 |
307 (7.2%) |
990 (9.1%) |
<0.001 |
| Warfarin |
309 (10%) |
793 (9.8%) |
0.39 |
281 (6.6%) |
913 (8.4%) |
<0.001 |
| DOAC |
17 (1.2%) |
62 (1.5%) |
0.43 |
27 (1.3%) |
77 (1.4%) |
0.76 |
Proton pump inhibitor or histamine
type-2 receptor blocker* |
2,251 (75%) |
6,100 (75%) |
0.87 |
2,498 (59%) |
6,124 (56%) |
0.005 |
| Proton pump inhibitor |
1,640 (55%) |
4,284 (53%) |
0.052 |
1,779 (42%) |
4,315 (40%) |
0.01 |
| H2 blocker |
624 (21%) |
1,841 (23%) |
0.046 |
734 (17%) |
1,855 (17%) |
0.75 |
Continuous variables are expressed as mean±standard deviation, or median (interquartile range). Categorical variables are expressed as number (percentage). *Risk-adjusting variables for the Cox proportional hazard models beyond 30 days, and during the entire follow-up period. †Risk-adjusting variables for the Cox proportional hazard models within 30 days. There were missing values for BMI in 665 patients (ACS: 506 patients, stable CAD: 159 patients), for LVEF in 4,028 patients (ACS: 2,050 patients, stable CAD: 1,978 patients), for eGFR in 209 patients (ACS: 122 patients, stable CAD: 87 patients), for hemoglobin level in 224 patients (ACS: 137 patients, stable CAD: 87 patients), for platelet count in 136 patients (ACS: 59 patients, stable CAD: 77 patients). The missing values for these variables except for LVEF were imputed as “normal” in the binary classification, because data would have been available if abnormalities were suspected. On the other hand, the missing values for LVEF were not imputed in the categorical classification, because the number of missing values for LVEF was substantial. ACE inhibitor/ARB, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CTO, chronic total occlusion; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LMCA, left main coronary artery; LVEF, left ventricular ejection fraction; NSTEACS, non-ST-segment-elevation ACS; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment-elevation myocardial infarction.
We also conducted landmark analyses at 30 days after the index procedure to distinguish early events within 30 days, and late events beyond 30 days. In the models of within 30 days, we incorporated 20 clinically relevant risk-adjusting variables excluding 5 variables about medications at discharge from the 25 variables in the full Cox model as listed in Table 1. We conducted a subgroup analysis for the primary outcome measure stratified by age tertiles. We also conducted a sensitivity analysis for the primary outcome measure stratified by each cohort to confirm the consistency of the results in each cohort pooled in this study.
All analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). All reported P values are two-tailed, and P<0.05 was considered statistically significant.
Results
Baseline Characteristics
Among the patients with ACS, women were much older and had a smaller body mass than the men. Women had more comorbidities, such as hypertension, insulin-treated diabetes mellitus, prior HF, prior stroke, renal failure, atrial fibrillation, anemia, and malignacy, than men. In contrast, women less often had a current smoking habit than men. Women as compared with men more often had HF at admission for ACS than men. There were no large differences in procedural characteristics between women and men, except for smaller maximum stent sizes in women. Guideline-directed medications such as statins, β-blockers, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers were less often prescribed for women than for men (Table 1). Among the patients with stable CAD, women were also older with smaller body mass index than men. However, the age difference between men and women was smaller in patients with stable CAD than in patients with ACS. Women as compared with men more often had hypertension, insulin-treated diabetes mellitus, HF at admission, renal failure, and anemia, while men more often had a current smoking habit, prior MI, prior stroke, peripheral vascular disease, atrial fibrillation, chronic obstructive pulmonary disease, liver cirrhosis, and malignancy. Regarding the procedural characteristics, the prevalence of the radial approach and target of chronic total occlusion was lower, and maximum stent size was smaller in women than in men. Women as compared with men more often received statins and less often received anticoagulants than men (Table 1).
Clinical Outcomes During Entire Follow-up
The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS stratum (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD stratum (14.2% and 15.8%, log rank P=0.005) (Figure 2, Table 2). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk in the stable CAD stratum but not in the ACS stratum (HR: 0.75, 95% CI: 0.69–0.82, P<0.001, and HR: 0.92, 95% CI: 0.84–1.01, P=0.07, respectively) (Table 2). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002, Table 2). The favorable survival outcome in women relative to men was mainly driven by the lower risk for noncardiovascular death (Table 2).
Table 2. Clinical Outcomes Among Patients With ACS and Stable CAD Comparing Women and Men During Entire Follow-up
| Endpoints |
Women |
Men |
Crude HR
(95% CI) |
Crude
P value |
Adjusted HR
(95% CI) |
Adjusted
P value |
Interaction
P value |
No. of patients with event
(cumulative 5-year
incidence, %) |
| All-cause death |
| ACS |
852
(26.2%) |
1,563
(17.9%) |
1.61
(1.48–1.75) |
<0.001 |
0.92
(0.84–1.01) |
0.07 |
0.002 |
| Stable CAD |
681
(14.2%) |
1,987
(15.8%) |
0.88
(0.81–0.96) |
0.005 |
0.75
(0.69–0.82) |
<0.001 |
|
| Cardiovascular death |
| ACS |
564
(18.3%) |
894
(10.7%) |
1.83
(1.65–2.04) |
<0.001 |
1.04
(0.92–1.16) |
0.56 |
0.30 |
| Stable CAD |
382
(8.3%) |
908
(7.5%) |
1.08
(0.96–1.22) |
0.19 |
0.91
(0.80–1.04) |
0.16 |
|
| Noncardiovascular death |
| ACS |
234
(9.7%) |
556
(8.0%) |
1.30
(1.13–1.50) |
<0.001 |
0.77
(0.66–0.90) |
0.001 |
0.01 |
| Stable CAD |
248
(6.4%) |
885
(9.0%) |
0.71
(0.63–0.81) |
<0.001 |
0.61
(0.54–0.70) |
<0.001 |
|
| Myocardial infarction |
| ACS |
148
(5.3%) |
450
(5.6%) |
0.97
(0.80–1.16) |
0.72 |
1.02
(0.83–1.24) |
0.87 |
0.58 |
| Stable CAD |
210
(4.8%) |
537
(4.7%) |
1.01
(0.86–1.19) |
0.90 |
0.97
(0.82–1.15) |
0.76 |
|
| Definite stent thrombosis* |
| ACS |
45
(1.7%) |
150
(1.9%) |
0.89
(0.64–1.24) |
0.48 |
1.13
(0.79–1.63) |
0.50 |
0.37 |
| Stable CAD |
29
(0.8%) |
99
(0.9%) |
0.76
(0.50–1.14) |
0.18 |
0.87
(0.56–1.35) |
0.53 |
|
| Stroke |
| ACS |
224
(8.2%) |
486
(6.0%) |
1.36
(1.16–1.6) |
<0.001 |
1.00
(0.84–1.18) |
0.97 |
0.20 |
| Stable CAD |
267
(6.1%) |
717
(6.2%) |
0.96
(0.83–1.10) |
0.53 |
0.89
(0.76–1.03) |
0.11 |
|
| Hospitalization for heart failure |
| ACS |
344
(12.5%) |
562
(7.1%) |
1.85
(1.62–2.12) |
<0.001 |
1.21
(1.04–1.40) |
0.01 |
0.11 |
| Stable CAD |
424
(9.9%) |
894
(7.8%) |
1.23
(1.10–1.38) |
<0.001 |
1.05
(0.93–1.19) |
0.44 |
|
| Major bleeding |
| ACS |
559
(19.1%) |
1,056
(13.1%) |
1.58
(1.42–1.75) |
<0.001 |
1.19
(1.06–1.33) |
0.003 |
0.47 |
| Stable CAD |
585
(13.7%) |
1,290
(11.5%) |
1.19
(1.08–1.31) |
<0.001 |
1.15
(1.04–1.28) |
0.007 |
|
| Any coronary revascularization |
| ACS |
742
(28.3%) |
2,605
(34.3%) |
0.80
(0.74–0.87) |
<0.001 |
0.84
(0.77–0.91) |
<0.001 |
0.43 |
| Stable CAD |
1,158
(27.4%) |
3,470
(32.1%) |
0.84
(0.78–0.89) |
<0.001 |
0.88
(0.82–0.95) |
0.001 |
|
| Target vessel revascularization |
| ACS |
546
(20.7%) |
1,984
(26.1%) |
0.78
(0.71–0.85) |
<0.001 |
0.83
(0.75–0.91) |
<0.001 |
0.56 |
| Stable CAD |
813
(19.2%) |
2,525
(23.3%) |
0.81
(0.75–0.88) |
<0.001 |
0.88
(0.81–0.95) |
0.002 |
|
The number of patients with event was counted until the end of follow-up. Cumulative incidence was estimated by the Kaplan-Meier method, and was represented by that at 5 years. The number of patients with event and the HRs with 95% CIs of women relative to men for clinical outcomes were estimated throughout the entire follow-up period using Cox proportional hazard models. Myocardial infarction was adjudicated based on the ARTS definition. Major bleeding was defined as GUSTO moderate/severe bleeding. Definite stent thrombosis was adjudicated based on the ARC definition, and was analyzed only for patients who underwent PCI with stent implantation (2,992 patients among women with ACS, 8,127 patients among men with ACS; 4,266 patients among women with stable CAD, 1,0931 patients among men with stable CAD). Scheduled staged PCI was not regarded as afollow-up event, but as the index procedure. ACS, acute coronary syndrome; CAD, coronary artery disease; PCI, percutaneous coronary intervention.
The cumulative 5-year incidence of major bleeding was significantly higher in women than in men in both the ACS and stable CAD strata (19.1% and 13.1%, log rank P<0.001, and 13.7% and 11.5%, log rank P<0.001, respectively) (Figure 3). After adjusting confounders, the bleeding risk of women relative to men remained significant in both strata (HR: 1.19, 95% CI: 1.06–1.33, P=0.003, HR: 1.15, 95% CI: 1.04–1.28, P=0.007, respectively) (Table 2).
The cumulative 5-year incidence of hospitalization for HF was significantly higher in women than in men in both the ACS and stable CAD strata (12.5% and 7.1%, log rank P<0.001, and 9.9% and 7.8%, P<0.001, respectively) (Supplementary Figures 1,2). After adjusting confounders, the excess risk of women relative to men for hospitalization for HF remained significant in the ACS stratum, but not in the stable CAD stratum (HR: 1.21, 95% CI: 1.04–1.40, P=0.01, and HR: 1.05, 95% CI: 0.93–1.19, P=0.44, respectively) (Table 2). Women as compared with men were associated with significantly lower adjusted risk for any coronary revascularization, and target vessel revascularization in both the ACS and stable CAD strata. The risks of women relative to men were not significant for other secondary outcome measures in both strata (Table 2, Supplementary Figures 1,2).
In the subgroup analysis by age tertiles, there was no significant interaction between age tertiles and the mortality risk of women relative to men in both the ACS and stable CAD strata (Table 3).
Table 3. Subgroup Analysis for All-Cause Death Compared Between Women and Men Among Patients With ACS or Stable CAD Stratified by Age Tertiles
| Endpoints |
Women |
Men |
Crude HR
(95% CI) |
Crude
P value |
Adjusted HR
(95% CI) |
Adjusted
P value |
Interaction
P value |
No. of patients with event
(cumulative incidence, %) |
| ACS |
| Age ≤70 |
106
(10.5%) |
525
(9.6%) |
1.10
(0.89–1.35) |
0.38 |
0.95
(0.76–1.18) |
0.62 |
0.39 |
| 70<Age≤78 |
188
(20.1%) |
445
(23.6%) |
0.89
(0.75–1.06) |
0.19 |
0.88
(0.74–1.05) |
0.16 |
|
| Age >78 |
558
(43.4%) |
593
(44.9%) |
0.99
(0.89–1.12) |
0.93 |
0.86
(0.76–0.98) |
0.02 |
|
| Stable CAD |
| Age ≤70 |
139
(7.9%) |
173
(8.5%) |
0.85
(0.71–1.02) |
0.08 |
0.82
(0.68–0.99) |
0.04 |
0.29 |
| 70<Age≤78 |
203
(12.2%) |
704
(19.4%) |
0.60
(0.51–0.70) |
<0.001 |
0.69
(0.59–0.82) |
<0.001 |
|
| Age >78 |
339
(25.4%) |
660
(36.9%) |
0.66
(0.58–0.76) |
<0.001 |
0.71
(0.61–0.81) |
<0.001 |
|
The number of patients with event was counted until the end of follow-up. Cumulative incidences of entire follow-up and beyond 30 days were estimated by the Kaplan-Meier method, and represented by that at 5 years. The number of patients with event and HRs with 95% CIs of women relative to men for clinical outcomes were estimated throughout the entire follow-up period using Cox proportional hazard models. ACS, acute coronary syndrome; CAD, coronary artery disease.
The cumulative 30-day incidence of all-cause death was significantly higher in women than in men (7.4% and 4.1%, log rank P<0.001) among the patients with ACS. In patients with stable CAD, it was very low and similar between women and men (0.4% and 0.4%, log rank P=0.87) (Supplementary Figure 3). However, after adjusting confounders, the excess mortality risk of women relative to men was no longer significant among the patients with ACS (HR: 1.14, 95% CI: 0.94–1.37, P=0.18) (Supplementary Figure 3, Supplementary Table 1). The cumulative 30-day incidence of major bleeding was significantly higher in women than in men in both the ACS and stable CAD strata (10.4% and 5.5%, log rank P<0.001, and 3.5% and 1.6%, log rank P<0.001, respectively) (Supplementary Figure 4). Even after adjusting confounders, the excess risk of women relative to men remained significant for major bleeding in both strata (HR: 1.45, 95% CI: 1.24–1.70, P<0.001, and HR: 1.96, 95% CI: 1.56–2.48, P<0.001, respectively) (Supplementary Figure 4, Supplementary Table 1).
The results of clinical outcomes beyond 30 days were largely consistent with those during the entire follow-up (Supplementary Table 2). In the sensitivity analysis stratified by the 2 cohorts, the results in Cohort-2 and Cohort-3, respectively, were also fully consistent with those in the main analysis (Supplementary Table 3).
Discussion
The main findings of this study evaluating the sex difference in the baseline characteristics and clinical outcomes after PCI were that women compared with men had significantly lower adjusted long-term mortality risk after PCI among the patients with stable CAD, but not in those with ACS. There was a significant interaction between the clinical presentation of ACS or stable CAD and the mortality risk of women relative to men.
During the past several decades, many studies have evaluated the effect of sex on the difference in mortality risk in patients with CAD. Several studies have suggested that the mortality risk is higher in women compared with men among patients with acute MI. However, that result might be largely explained by the greater burden of comorbidities, longer delays to reperfusion, lower prevalence of angiography and revacularization, and lower rate of guideline-recommended medical therapy in women.8–16 Therefore, the sex gap in patients with CAD remains controvertial. Moreover, the effect of the presentation of CAD on the sex gap has not been adequately evaluated, although a population-based study in patients with angiographic evidence of CAD has suggested that women more often had adverse outcomes, angina admission in particular, than men both for ACS and stable CAD, and the magnitude of the excess risk of women relative to men was greater in ACS than in stable CAD.17 In the present study, we only enrolled patients who underwent PCI for either ACS or stable CAD. We evaluated the risk difference between sex not only for death, but also for other clinical outcomes such as hospitalization for HF, stroke, MI and major bleeding, stratified by the clinical presentation of ACS or stable CAD. We conducted extensive statistical adjustment by potential confounders, including baseline comorbidities as well as procedure characteristics and medications, to estimate the risk difference between women and men.
Regarding the baseline characteristics and medications, women more often had cormobidities and they were administered guideline-directed medications less often in patients with ACS, which were consistent with prior studies.8–16 However, these trends were less pronounced in patients with stable CAD than in those with ACS, suggesting that the characteristics of women compared with men might differ according to each presentation of CAD. Particularly, it is noteworthy that the age difference between women and men was greater in the ACS than in the stable CAD stratum. Women with ACS were older than women with stable CAD, whereas men with ACS were younger than men with stable CAD, suggesting that the difference between men and women in the propensity to develop ACS might be greater than that to develop stable CAD. Among the factors predisposing to the development of coronary atherosclerosis, some factors more prevalent in men than in women such as current smoking habit might be important for the development of ACS.
Regarding short-term mortality, a previous meta-analysis reported higher adjusted risk for in-hospital death in women compared with men among STEMI patients treated by primary PCI.27 In the present study, the unadjusted excess 30-day mortality risk of women relative to men was substantial among the patients with ACS. Indeed, women as compared with men more often had HF at admission for ACS, which might be closely related to older age in women than in men. However, after extensive adjustment for potential confounders, the excess 30-day mortality risk of women relative to men was no longer significant, suggesting it was mostly confounded by the differences in clinical profiles and comorbidities between women and men.
Regarding long-term mortality, several studies suggest the excess mortality risk in women compared with men among patients with acute MI attenuated during long-term follow-up, and was no longer significant after adjusting counfounders.1,18,27 In the present study, the lower long-term mortality risk in women compared with men was significant only in patients with stable CAD, with significant interaction between sex and presentaiton. Studies evaluating the sex gap in patients with stable CAD are scarce and the results are inconsistent across studies.18,19 The lower mortality risk of women relative to men is mainly driven by their lower risk for noncardiovascular death, suggesting it is simply related to the longevity of women compared with men in general.
We found a significantly higher bleeding risk in women compared with men irrespective of the presentations, consitent with prior studies.16,18,28 A prior study reported post-PCI bleeding was more common and associated with higher in-hospital mortality rates in women compared with men.29 Therefore, strategies to reduce bleeding after coronary revascularization might particularly be relevant for women. We also found a significant long-term excess risk of women relative to men for hospitalization for HF among patients with ACS, which was consistent wih a prior study.1 More attention needs to be given to preventing HF in women.
Study Limitations
First, we pooled the patients from 2 cohorts with different inclusion periods. However, both cohorts had the same inclusion criteria and the same definitions of the clinical outcome measures. Moreover, the sensitivity analysis stratified by each cohort indicated fully consistent results. Second, we included only patients who underwent PCI. The choice of PCI by the cardiologist might differ for women and men. However, exclusive enrollment of patients who underwent PCI might be more relevant for assessing the true sex difference in clinical outcomes of patients with CAD. Third, we included only Japanese patients, and therefore, the influence of ethnicity was not addressed. Finally, there might be some residual unmeasured confounders.
Conclusions
Women compared with men had a significantly lower adjusted mortality risk after PCI in patients with stable CAD, but not those with ACS.
Acknowledgments
This study was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan) and the Pharmaceuticals and Medical Devices Agency in Japan (Tokyo, Japan).
Disclosures
Dr. Kimura reports to the advisory board of Abbott Vascular, has received honoraria from Kowa, Bristol-Myers Squibb, and Boston Scientific, and has received grants from Otsuka, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Bayer, Takeda Pharmaceutical, and Astellas.
IRB Information
The protocols for the CREDO-Kyoto PCI/CABG Registry Cohort-2 and Cohort-3 were approved by the human research ethics committees of the Kyoto University Graduate School of Medicine, Reference numbers: E42, E2400.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-22-0517
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