Sex Differences in Long-Term Clinical Outcomes in Patients With Atrial Fibrillation Undergoing Coronary Stent Implantation

Yukiko Matsumura-Nakano; Hiroki Shiomi; Takeshi Morimoto; Satoshi Shizuta; Kyohei Yamaji; Hirotoshi Watanabe; Yusuke Yoshikawa; Tomohiko Taniguchi; Tetsuma Kawaji; Masahiro Natsuaki; Takashi Akasaka; Keiichi Hanaoka; Kazushige Kadota; Ken Kozuma; Kengo Tanabe; Yoshihisa Nakagawa; Toshiya Muramatsu; Yoshihiro Morino; Kenji Ando; Takeshi Kimura

doi:10.1253/circj.CJ-17-1278

Abstract

Background: Patients with concomitant atrial fibrillation (AF) and coronary stenting are at high risk for both cardiovascular and bleeding events. We aimed to evaluate the influence of sex on long-term clinical outcomes in this patient subset.

Methods and Results: We identified 1,450 patients with AF and coronary stenting in a patient-level pooled database from 3 Japanese studies, and compared 3-year clinical outcomes between men and women (n=1,075, and n=375, respectively). The cumulative 3-year incidence of all-cause death was significantly higher in women than in men (26.5% vs. 17.2%, log-rank P<0.001), although after adjusting for confounders, the excess mortality risk of women relative to men was no longer significant (hazard ratio (HR): 1.12, 95% confidence interval (CI): 0.85–1.46, P=0.42). There were no significant differences in the adjusted 3-year risks for myocardial infarction or stroke between men and women (HR: 1.25, 95% CI: 0.62–2.40, P=0.52, and HR: 1.15, 95% CI: 0.75–1.74, P=0.52, respectively). However, both the cumulative 3-year incidence of and adjusted risk for major bleeding were significantly higher in women than in men (17.0% vs. 11.3%, log-rank P=0.002, and HR: 1.47, 95% CI: 1.03–2.07, P=0.03).

Conclusions: Among patients with concomitant AF and coronary stenting, there were no significant differences in the adjusted 3-year risks for all-cause death, myocardial infarction, and stroke between men and women. However, women as compared with men were associated with excess adjusted risk for major bleeding.

Patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI) using coronary stents are known to be at high risk for both cardiovascular and bleeding events. Optimal antithrombotic therapy for those patients is still under debate.¹^–⁶ The influence of sex difference on clinical outcomes in cardiovascular disease is also controversial.⁷^–¹³ Most previous studies in patients with coronary artery disease (CAD) have reported that women had significantly higher observed mortality rates than men. However, there are conflicting reports regarding the higher mortality risk of women relative to men after adjusting for age and comorbidities.⁸^,¹¹^,¹⁴^–¹⁶ Several studies have reported that among AF patients women as compared with men were associated with significantly higher risk for stroke, but not for death.⁷^,⁹^,¹²^,¹⁷ However, there is no previous study evaluating the influence of sex on long-term clinical outcomes in patients with concomitant AF and coronary stenting. Therefore, we sought to evaluate the influence of sex on the long-term clinical outcomes of AF patients who underwent PCI with coronary stenting in a large pooled cohort from 3 Japanese studies.

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Methods

Study Population

We constructed a patient-level pooled database of 22,386 patients from 3 Japanese coronary revascularization studies conducted by the same group of investigators: the Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG (coronary artery bypass grafting) registry cohort-2, n=15,939;¹⁸ Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial (RESET), n=3,206;¹⁹ and NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial (NEXT), n=3,241.²⁰ The study designs and main results of the 3 studies have been published and are summarized in Table S1. Briefly, the CREDO-Kyoto registry cohort-2 was a multicenter observational registry that enrolled consecutive patients undergoing their first coronary revascularization (January 2005–December 2007).¹⁸^,²¹ RESET was a randomized controlled trial (RCT) that compared sirolimus-eluting stent (SES) with everolimus-eluting stent (EES) without any exclusion criteria (February–July 2010).¹⁹^,²² NEXT was a RCT that compared EES with biolimus-eluting stent (BES) without any exclusion criteria (May–October 2011).²⁰ The follow-up duration was 5 years in the CREDO-Kyoto PCI/CABG registry cohort-2, and 3 years in RESET and NEXT. For the present analysis, the follow-up period was truncated at 3 years to standardize the follow-up duration.

Among the 22,386 patients in this pooled cohort, we identified 18,580 CAD patients who underwent PCI with stent implantation after excluding 2,782 patients with CABG, 909 patients who had PCI without stent implantation, 114 patients who refused study participation and 1 patient with duplicate enrollment. There were 1,450 (7.8%) patients with concomitant AF, who constituted the current study population (men: n=1,075; women: n=375) (Figure 1).

Figure 1.

Study flow chart. AF, atrial fibrillation; CABG, coronary artery bypass grafting; CREDO-Kyoto, Coronary REvascularization Demonstrating Outcome Study in Kyoto; NEXT, NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial; PCI, percutaneous coronary intervention; RESET, Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial.

Definitions and Endpoints

Baseline clinical characteristics, such as hypertension, current smoking, heart failure (HF), prior myocardial infarction (MI) and malignancy, were regarded as present when these diagnoses were recorded in hospital charts. Elderly patients were defined as ≥75 years of age. Diabetes was defined as treatment with oral hypoglycemic agents and/or insulin, prior clinical diagnosis of diabetes, glycated hemoglobin level ≥6.5%, or blood glucose level 200 mg/dL. Prior stroke was defined as ischemic or hemorrhagic stroke, including both symptomatic and asymptomatic stroke, detected by noninvasive imaging modalities. Peripheral vascular disease was regarded to be present when carotid, aortic, or other peripheral vascular disease was being treated or scheduled for surgical or endovascular intervention. Left ventricular ejection fraction (LVEF) was measured either by contrast left ventriculography or echocardiography. Patients with LVEF ≤40% were regarded as having LV dysfunction. Anemia was defined as blood hemoglobin level <11.0 g/dL. Baseline medications were regarded as present if prescribed during the index hospitalization.

The outcome measures in the current analyses included all-cause death, cardiac death, non-cardiac death, MI, definite stent thrombosis (ST), stroke, hospitalization for HF, major bleeding, and any coronary revascularization. Death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. Any death during the index hospitalization for coronary revascularization was regarded as cardiac death. MI was defined according to the Arterial Revascularization Therapies Study (ARTS) definition in the CREDO-Kyoto PCI/CABG registry cohort-2 and was defined according to the Academic Research Consortium (ARC) definition in RESET and NEXT.²³^,²⁴ The definitions of endpoints other than MI were identical across the 3 studies. ST was defined according to the definition of the ARC.²⁴ Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting >24 h. Hospitalization for HF was defined as hospitalization for worsening HF requiring intravenous drug therapy. Bleeding was defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification.²⁵ GUSTO moderate or severe bleeding was adjudicated as a major bleeding event. Any coronary revascularization was defined as either PCI or CABG for any reason. All the clinical events were adjudicated by independent clinical event committees in each study. Each study protocol was approved by the institutional review boards in all the participating centers.

Antithrombotic Therapy

Procedural anticoagulation was achieved with unfractionated heparin following the local site protocols. The recommended antiplatelet regimen included aspirin (≥81 mg daily) indefinitely and thienopyridines (75 mg clopidogrel or 200 mg ticlopidine daily) for ≥3 months in RESET and NEXT. There was no specific protocol recommended antiplatelet therapy in the CREDO-Kyoto registry cohort-2 because of its retrospective observational study design. The actual duration of dual antiplatelet therapy (DAPT) and the use of anticoagulation drugs were left to the discretion of each attending physician in all the studies. During the enrollment period of the 3 studies, only warfarin was available as an oral anticoagulant (OAC). The status of antiplatelet therapy was evaluated throughout the follow-up period.

Data Collection for Baseline Characteristics and Follow-up Events

Demographic, angiographic, and procedural data were collected from hospital charts or hospital databases according to the prespecified definitions by the experienced clinical research coordinators from the independent clinical research organization (Research Institute for Production Development, Kyoto, Japan; Appendix S1) or by the site investigators. Collection of follow-up information was mainly conducted through review of hospital charts by the clinical research coordinators, 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. Complete 1- and 3-year clinical follow-up information was obtained for 99.2% and 97.0% of patients, respectively.

Statistical Analysis

Categorical variables are presented as number and percentage and were compared with the chi-square test. Continuous variables are expressed as mean±standard deviation (SD) or median with interquartile range (IQR). Continuous variables were compared using Student’s t-test or Wilcoxon rank sum test based on their distributions. Cumulative incidence was estimated by the Kaplan-Meier method and differences were assessed with the log-rank test. The effects of women relative to men for the individual endpoints were expressed as hazard ratios (HR) and their 95% confidence intervals (CI). We estimated the HR by Cox proportional hazard models adjusting for 19 clinically relevant factors listed in Table 1. Continuous variables were dichotomized by clinically meaningful reference values or median values. Proportional hazard assumptions for potential independent risk-adjusting variables were assessed on the plots of log (time) vs. log [-log (survival)] stratified by the variable, and the assumptions were verified to be acceptable for all the variables.

Table 1. Baseline Characteristics of the Study Patients With Concomitant AF and Coronary Stenting

Variables	Total (n=1,450)	Men (n=1,075)	Women (n=375)	P value
Clinical characteristics
Age, years	72.8±8.9	71.4±8.8	76.8±8.0	<0.001
≥75 years*	662 (45.7)	423 (39.4)	239 (63.7)	<0.001
BMI <25.0 kg/m²*	1,028 (70.9)	753 (70.1)	275 (73.3)	0.23
STEMI*	325 (22.4)	221 (20.6)	104 (27.7)	0.005
Hypertension	1,244 (85.8)	922 (85.8)	322 (85.9)	0.96
Diabetes mellitus*	549 (37.9)	398 (37.0)	151 (40.3)	0.27
DM on insulin therapy	110 (7.6)	72 (6.7)	38 (10.1)	0.04
Current smoking*	282 (19.4)	261 (24.3)	21 (5.6)	<0.001
HF*	566 (39.0)	391 (36.4)	175 (46.7)	<0.001
LVEF ≤40%	196 (15.6)	155 (16.6)	41 (12.6)	0.08
Prior MI*	256 (17.7)	197 (18.3)	59 (15.7)	0.25
Prior stroke*	267 (18.4)	198 (18.4)	69 (18.4)	0.99
Peripheral vascular disease*	130 (9.0)	107 (10.0)	23 (6.1)	0.02
eGFR <30 mL/min/1.73 m², without HD*	83 (5.7)	47 (4.4)	36 (9.6)	<0.001
HD*	84 (5.8)	56 (5.2)	28 (7.5)	0.12
Anemia (Hb <11 g/dL)*	224 (15.4)	125 (11.6)	99 (26.4)	<0.001
Malignancy*	139 (9.6)	107 (10.0)	32 (8.5)	0.42
Paroxysmal AF	864 (64.5)	630 (62.5)	234 (70.5)	0.008
CHADS₂ score	2.4±1.2	2.3±1.3	2.7±1.2	<0.001
CHA₂DS₂-VASc score	4.0±1.7	3.6±1.6	5.2±1.4	<0.001
High (≥2)	1,378 (95.0)	1,003 (93.3)	375 (100)	<0.001
Procedural characteristics
No. of target lesions	1 (1–2)	1 (1–2)	1 (1–2)	0.41
Target of unprotected LMCA	66 (4.6)	48 (4.5)	18 (4.8)	0.79
Target of proximal LAD*	785 (54.1)	581 (54.1)	204 (54.4)	0.91
Target of CTO	134 (9.2)	99 (9.2)	35 (9.3)	0.94
Use of DES	961 (66.2)	723 (67.3)	238 (63.5)	0.18
1st-generation DES*	634 (43.7)	456 (42.4)	178 (47.5)	0.09
2nd-generation DES*	333 (23.0)	270 (25.1)	63 (16.8)	<0.001
Total stent length, mm	28 (18–44)	28 (18–43)	28 (18–46)	0.35
Medications at hospital discharge
Antiplatelet therapy
Thienopyridine	1,430 (98.6)	1,062 (98.8)	368 (98.1)	0.36
Aspirin	1,427 (98.4)	1,061 (98.7)	366 (97.6)	0.16
Cilostazol	218 (15.0)	165 (15.4)	53 (14.1)	0.57
Other medications
Statins*	694 (47.9)	511 (47.5)	183 (48.8)	0.67
β-blockers*	595 (41.0)	446 (41.5)	149 (39.7)	0.55
ACEI/ARB*	898 (61.9)	663 (61.7)	235 (62.7)	0.73
Nitrates	431 (29.7)	309 (28.7)	122 (32.5)	0.17
CCBs	622 (42.9)	461 (42.9)	161 (42.9)	0.99
Warfarin*	703 (48.5)	558 (51.9)	145 (38.7)	<0.001

Categorical variables are presented as number (percentage), and continuous variables are presented as mean±standard deviation or median and 25–75th percentiles. Values are missing for EF in 190 patients, and for clinical pattern of atrial fibrillation in 110 patients. *Risk-adjusting variables selected for Cox proportional hazard models. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BMI, body mass index; CCB, calcium-channel blocker; CTO, chronic total occlusion; DES, drug-eluting stent; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HD, hemodialysis; HF, heart failure LAD, left anterior descending artery; LMCA, left main artery disease; LVEF, Left ventricular ejection fraction; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

To assess the different effect of sex difference on the risks for death and major bleeding, we also conducted landmark analyses at 30 days after the index PCI.

All statistical analyses were conducted using JMP 12.0 software (SAS Institute Inc., Cary, NC, USA). All reported P values were two-tailed, and P<0.05 was considered statistically significant.

Results

Baseline Characteristics

The current study population included a large proportion of patients with advanced age and comorbidities (Table 1). Mean CHADS₂ and CHA₂DS₂-VASc scores were 2.4±1.2 and 4.0±1.7, respectively. The prevalence of CHA₂DS₂-VASc score ≥2 was 95.0% (Figure 2). Warfarin was prescribed only in 48.5% of patients; aspirin and thienopyridine were prescribed in the vast majority of patients.

Figure 2.

(A–C) Distribution of CHA₂DS₂-VASc scores in the entire cohort, and in men and women. SD, standard deviation; VKA, vitamin K antagonist.

There were several important differences between men and women in the baseline clinical characteristics. Women as compared with men were older and more often had ST-segment elevation MI presentation, insulin-treated diabetes mellitus, HF, renal dysfunction without hemodialysis, and anemia, but less often had current smoking and peripheral vascular disease. Both the CHADS₂ and CHA₂DS₂-VASc scores were significantly higher in women than in men (2.7±1.2 vs. 2.3±1.3, P<0.001 and 5.2±1.4 vs. 3.6±1.6, P<0.001, respectively). Lesion and procedural characteristics were comparable between men and women. Regarding the medication at hospital discharge, the prescription rate of warfarin was significantly lower in women than in men (38.7% vs. 51.9%, P<0.001) (Table 1).

Long-Term Clinical Outcomes in Men and Women

The cumulative 3-year incidence of all-cause death was significantly higher in women than in men (26.5% vs. 17.2%, log-rank P<0.001) (Figure 3). After adjusting for confounders, the excess mortality risk of women relative to men was no longer significant (HR: 1.12, 95% CI: 0.85–1.46, P=0.42) (Table 2). The cumulative 3-year incidence of cardiac death was significantly higher in women than in men (15.8% vs. 7.9%, log-rank P<0.001), and the adjusted risk for cardiac death tended to be higher in women than in men (HR: 1.37, 95% CI: 0.93–2.01, P=0.11). The cumulative incidence of all-cause death was significantly higher in women than in men both within and beyond 30 days after the index coronary stent implantation (4.8% vs. 2.4%, log-rank P=0.02, and 22.8% vs. 15.2%, log-rank P<0.001, respectively), whereas the excess adjusted risks of women relative to men for mortality within and beyond 30 days were no longer significant (HR 1.46, 95% CI 0.72–2.93, P=0.29, and HR 1.07, 95% CI 0.79–1.43, P=0.67, respectively) (Figure S1, Table S2). The cumulative 3-year incidences of and adjusted risk for MI and stroke were not significantly different between men and women (3.5% vs. 4.6%, log-rank P=0.40, HR: 1.25, 95% CI: 0.62–2.40, P=0.52; 8.7% vs. 10.7%, log-rank P=0.21, HR: 1.15, 95% CI: 0.75–1.74, P=0.52, respectively). The cumulative 3-year incidence of hospitalization for HF was significantly higher in women than in men (16.7% vs. 11.4%, log-rank P=0.008), although the excess adjusted risk of women relative to men for hospitalization for HF was no longer significant (HR 1.09, 95% CI 0.76–1.55, P=0.63). The cumulative 3-year incidence of major bleeding was significantly higher in women than in men, and the excess risk of women relative to men for major bleeding remained significant even after adjusting for confounders (17.0% vs. 11.3%, log-rank P=0.002; HR: 1.47, 95% CI: 1.03–2.07, P=0.03). The cumulative incidence of and adjusted risk for major bleeding were significantly higher in women than in men within 30 days after the index coronary stent implantation (7.5% vs. 3.2%, log-rank P<0.001; HR 2.39, 95% CI 1.34–4.26, P=0.003), but not significantly different between men and women beyond 30 days (8.4% vs. 10.3%, log-rank P=0.26; HR 1.17, 95% CI 0.74–1.81, P=0.50) (Figure S1, Table S2). The cumulative 3-year incidence of any coronary revascularization tended to be lower in women than in men, and there was a borderline significant difference in the adjusted risk for any coronary revascularization between men and women (24.6% vs. 19.5%, log-rank P=0.08; HR: 0.75, 95% CI: 0.56–0.996, P=0.047).

Figure 3.

(A–D) Cumulative incidences of clinical outcome measures for all-cause death, myocardial infarction (MI), stroke and major bleeding through 3-year follow-up: men vs. women.

Table 2. Crude and Adjusted 3-Year Clinical Outcomes: Men vs. Women

Endpoints	Total (n=1,450)	Men (n=1,075)	Women (n=375)	Crude HR (95% CI)	P value	Adjusted HR (95% CI)	P value
All-cause death	281 (19.6)	183 (17.2)	98 (26.5)	1.64 (1.28–2.09)	<0.001	1.12 (0.85–1.46)	0.42
Cardiac death	137 (9.9)	81 (7.9)	56 (15.8)	2.23 (1.65–3.00)	<0.001	1.37 (0.93–2.01)	0.11
Non-cardiac death	100 (7.6)	67 (6.7)	33 (10.2)	1.52 (0.99–2.28)	0.06	0.99 (0.62–1.56)	0.97
MI	50 (3.8)	35 (3.5)	15 (4.6)	1.30 (0.69–2.33)	0.41	1.25 (0.62–2.40)	0.52
Definite ST	13 (0.9)	9 (0.9)	4 (1.2)	1.31 (0.35–4.02)	0.66	–	–
Stroke	122 (9.2)	86 (8.7)	36 (10.7)	1.28 (0.86–1.87)	0.22	1.15 (0.75–1.74)	0.52
Ischemic stroke	96 (7.2)	65 (6.5)	31 (9.2)	1.46 (0.94–2.22)	0.09	1.24 (0.77–1.96)	0.37
Hemorrhagic stroke	26 (2.0)	21 (2.2)	5 (1.6)	0.73 (0.24–1.78)	0.51	–	–
Hospitalization for HF	169 (12.7)	113 (11.4)	56 (16.7)	1.54 (1.11–2.11)	0.01	1.09 (0.76–1.55)	0.63
Major bleeding	175 (12.8)	115 (11.3)	60 (17.0)	1.62 (1.18–2.21)	0.003	1.47 (1.03–2.07)	0.03
Any coronary revascularization	310 (23.3)	245 (24.6)	65 (19.5)	0.79 (0.59–1.03)	0.08	0.75 (0.56–0.996)	0.047

Data are presented as number of events with cumulative incidences, or hazard ratio (HR) and 95% confidence interval (CI) for clinical endpoints of women relative to men. Cumulative incidences were estimated by the Kaplan-Meier method. HF, heart failure; MI, myocardial infarction; ST, stent thrombosis.

The prescription rates of DAPT at hospital discharge, 1-year and 3-year follow-up were 97.4%, 57.3% and 37.7%, respectively, and were not significantly different between men and women (97.7% vs. 96.5%, P=0.25, 58.1% vs. 54.9%, P=0.31; 37.6% vs. 38.0%, P=0.91, respectively).

Discussion

The main findings of the current study evaluating the sex differences in AF patients undergoing coronary stenting were as follows: (1) women as compared with men more often had high-risk features such as advanced age, insulin-treated diabetes mellitus, renal failure, HF, anemia, and higher CHA₂DS₂-VASc score; (2) OACs were less often prescribed in women than in men despite their high risk for thromboembolic events; (3) there were no significant differences in the adjusted 3-year risks for all-cause death, MI, and stroke between men and women, but women as compared with men were associated with excess adjusted risk for major bleeding. AF was present in 7.8% of CAD patients who underwent PCI with stent implantation in the current study, which was consistent with previous Japanese studies.²⁶^,²⁷ Those CAD patients with AF were a higher risk population for both cardiovascular and bleeding events as compared with those without AF.¹^,² Recent clinical trials have evaluated various antithrombotic regimens in this patient subset with concomitant AF and coronary stenting.³^,⁴^,⁶^,²⁸ The WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) and PIONEER AF-PCI (Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention) studies have demonstrated significant reductions of bleeding events by the combination of OAC and P2Y₁₂ inhibitor without aspirin as compared with the triple therapy of OAC and DAPT.³^,⁴ Reflecting these results, current clinical guidelines recommend a short duration of triple or dual therapy with OAC and P2Y₁₂ inhibitor without aspirin in patients with concomitant AF and coronary stenting.²⁹^,³⁰ The current study clearly showed that the majority of patients with concomitant AF and coronary stenting had high risk of thromboembolic events requiring OAC, supporting the current guidelines recommendations of emphasizing OAC rather than DAPT. More recently, the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial demonstrated that even a very short duration of triple therapy with warfarin and DAPT (1 month after bare-metal stents and 3 months after drug-eluting stents) was still associated with a significantly higher risk for bleeding than dual therapy with dabigatran and P2Y₁₂ inhibitor.⁶

Regarding the sex differences in patients with concomitant AF and coronary stenting, women were much older and more often had serious comorbidities such as renal failure, HF, and anemia. Advanced age and these comorbidities are not only risk factors for thromboembolic events, but also for bleeding events. Concerns about bleeding might have led to less frequent warfarin use in women than in men, which could predispose them to the increased incidence of thromboembolic events. Regarding the long-term clinical outcomes, there were no significant differences in the adjusted risks for all-cause death, MI, and stroke between men and women. Therefore, female sex itself might not be related to the increased risk for cardiovascular events in patients with concomitant AF and coronary stenting. However, even if statistically not significant, women as compared with men had a numerically higher adjusted risk for all-cause death, MI, and stroke. Considering the limited sample size of the present study, we could not deny the possibility of a modestly higher risk of women relative to men for cardiovascular events. There are many possible mechanisms for the sex-related difference in the risk for cardiovascular events, including genetically different response to anticoagulation therapy, vascular physiology, influence of sex hormones, and different behavior regarding medical therapy.³¹^,³² Therefore, future larger studies are required to investigate the influence of sex on cardiovascular events in patients with concomitant AF and coronary stenting. Furthermore, women as compared with men were associated with significantly higher risk for bleeding. It also should be noted that the excess bleeding risk of women was seen within 30 days after the index coronary stent implantation, when the vast majority of patients were treated by either triple therapy or DAPT. Indeed, it was reported that female sex was an independent predictor of major bleeding within 30 days after PCI, which was strongly associated with an increased risk of subsequent death at 1 year.³³ Among patients with AF receiving vitamin K antagonists, women as compared with men were associated with higher risk for bleeding in the CARAF (Canadian Registry of Atrial Fibrillation) study,³⁴ and in a retrospective cohort analysis from Medicare’s National Stroke Project.³⁵ Furthermore, among patients undergoing PCI, women were also associated with higher risk for major bleeding in the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) registry,³⁶ and TRITON-TIMI 38 (Thrombolysis in Myocardial Infarction 38) studies.³⁷ Avoiding bleeding events might be an important consideration, particularly for women, when receiving intensive antithrombotic therapy. According to meta-analyses of DAPT after drug-eluting stent implantation, bleeding was associated with non-cardiovascular death, whereas ST was not associated with cardiovascular death.³⁸ It appears important to recognize that female patients with concomitant AF and coronary stenting may have high-risk features such as advanced age and severe comorbidities, and thus are at high risk for cardiovascular and bleeding events.

Study Limitations

First, despite the appropriate statistical adjustment for potential confounders, residual confounding factors might have affected the results of the current study. Second, we had no data about bleeding classification according to the Thrombosis in Myocardial Infarction (TIMI) criteria in the CREDO-Kyoto PCI/CABG registry cohort-2, and no data about bleeding classification according to the International Society on Thrombosis and Haemostasis (ISTH) and Bleeding Academic Research Consortium (BARC) criteria in all 3 studies included in this pooled analysis. The evaluation using different bleeding classifications such as the ISTH and BARC criteria might influence the results of this study. Third, the prescription rates of evidence-based medicines such as statins and β-blockers in this study were low according to the current standard, especially in the CREDO-Kyoto registry cohort-2 in which patients were enrolled between January 2005 and December 2007. Fourth, all the studies were conducted before the introduction of non-vitamin K OACs (NOACs) in Japan. The introduction of NOACs would have improved the prescription rate of OACs, especially in women, and might have influenced the relative clinical outcomes between women and men.¹³ Finally, we could not obtain information on the status of OAC prescription after hospital discharge, and time in therapeutic range for patients receiving warfarin, and therefore we could not evaluate different intensity of OAC therapies on clinical outcomes in the current study.

Conclusions

Among patients with concomitant AF and coronary stenting, there were no significant differences in the adjusted 3-year risks for all-cause death, MI, and stroke between men and women, although the women were older and more often had serious comorbidities than the men. Women as compared with men were associated with excess adjusted risk for major bleeding.

Acknowledgments

We appreciate the support and collaboration of the co-investigators participating in the CREDO-Kyoto PCI/CABG Registry Cohort-2, RESET and NEXT. We are indebted to the clinical research coordinators for data collection.

Disclosures

The CREDO-Kyoto PCI/CABG registry cohort-2 was supported by Pharmaceuticals and Medical Devices Agency in Tokyo, Japan. RESET was funded by Abbott Vascular in Tokyo, Japan. NEXT was funded by Terumo, in Tokyo, Japan. Dr. Tanabe has served on the advisory board of Terumo and Kaneka, and has received honoraria from Terumo and Kaneka. Dr. Kozuma and Dr. Kimura have served on the advisory board of Abbott Vascular and Terumo, and report research grants from Abbott Vascular. All the other authors report that they have no relationships relevant to the contents of this paper to disclose.

Supplementary Files

Supplementary File 1

Appendix S1. List of Clinical Research Coordinators

Figure S1. Landmark analyses (cumulative incidence curves) of (A) all-cause death and (B) major bleeding at 30 days: men vs. women.

Table S1. Designs and results of the 3 contributory studies, and baseline characteristics of the current study population

Table S2. Crude and adjusted risks for all-cause death and major bleeding within and beyond 30 days: men vs. women

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-1278

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