Women have a higher risk of adverse outcomes after percutaneous coronary intervention (PCI) than men. However, in acute coronary syndrome (ACS), long-term outcomes after contemporary PCI with drug-eluting stent (DES) have not been fully investigated. We aimed to test the impact of gender on outcomes in patients with ACS after PCI with DES. We analyzed all patients with ACS from the prospective NOBORI-2 trial who underwent PCI with a Nobori DES from 2008 through 2009 in 125 centers worldwide. End points of the study were target lesion failure, cardiac death, myocardial infarction (MI), and clinically driven target lesion revascularization, and major adverse cardiac events (composite of cardiac death, MI, and target vessel revascularization) at 1 year and yearly up to 5 years. There were 1,640 patients with ACS, 1,268 men (77%) and 372 women (23%). Compared to men, women were 5 years older and more frequently had co-morbidities such as diabetes mellitus and hypertension. There were no gender differences for cardiac death (1.3% vs 2.7%), MI (2.1% vs 3.2%), or target lesion revascularization (2.6% vs 3.8%) at 1 year after the procedure for men and women, respectively. The trend was the same at 2 years (cardiac death 2.0% vs 2.3%, MI 2.5% vs 3.5%, target lesion revascularization 3.2% vs 4.6%). Target lesion failure rates were 4.5% and 5.9% at 1 year and 5.7% and 7.3% at 2 years in men and women, respectively (p = NS). Multivariate analysis, which included age, hypertension, diabetes mellitus, and number of diseased vessels, showed that gender was not a predictor for outcome. There were no differences in bleeding or stent thrombosis rates. Relief from anginal symptoms was similar. The same rate of adherence to dual antiplatelet therapy was observed and reached 73% at 1 year and 31% at 2 years after the ACS event and PCI. In conclusion, although women had worse baseline characteristics, no differences in outcomes were observed between men and women treated for ACS with contemporary DES.
Drug-eluting stents (DESs) have changed the landscape of interventional cardiology with their high efficacy in preventing restenosis. The benefits of decreases in restenosis and repeat revascularization using DESs are independent of gender. In patients undergoing contemporary percutaneous coronary intervention (PCI), the procedural success is similar in women and men, although some have reported an increase in vascular and bleeding complications. The cause for these gender differences remains unclear. Data are limited in treated patients with acute coronary syndrome (ACS). The aim of the present study was to evaluate gender differences in outcomes and long-term (2-year) follow-up of patients treated for ACS in a large DES prospective trial.
Methods
The NOBORI-2 was a prospective, multicenter, observational single-arm study of the Nobori (Tokyo, Japan) DES system, which enrolled 3,067 patients. The present study included all patients from the NOBORI-2 trial with a diagnosis of ACS. Outcomes were stratified by gender.
Its primary objective was to validate, in a real-life setting, the safety and effectiveness of the Nobori DES system previously observed in randomized trials. Secondary objectives were to assess the long-term safety of the Nobori stent in a fully representative patient population with several patient/lesion subpopulations including gender differences, which are reported in the present study.
This was an all-comers trial of daily routine practice. Inclusion criteria for the present study were patients with ACS and coronary artery disease with reference vessel diameters from 2.5 to 3.5 mm, which according to hospital routine practice were eligible for PCI using DESs and were treated using the Nobori stent only. Exclusion criteria were according to the instructions for the use of the device.
ACS was defined as typical symptoms with ischemic electrocardiographic changes including ST-segment elevation and non–ST-segment elevation and/or laboratory evidence of myocardial damage.
The Nobori coronary stent is coated with a bioabsorbable polymer and the antiproliferative agent biolimus A9. Stents were implanted according to standard local clinical practice. No predilatation was required according to the protocol. Aspirin ≥75 mg/day was administrated to all patients before the procedure and indefinitely thereafter. A loading dose of clopidogrel was recommend pre- and periprocedurally and subsequently at 75 mg/day. Use of glycoprotein IIb/IIIa inhibitors was at the physician’s discretion. Stents were available in lengths of 8, 14, 18, 24, and 28 mm and in diameters of 2.5, 3.0, and 3.5 mm.
Lesion and device successes were defined as the attainment of <30% residual diameter stenosis by visual assessment. Procedural success was defined as achievement of a final diameter stenosis of <30% by visual assessment without the occurrence of death, myocardial infarction (MI), or repeat target lesion revascularization during the hospital stay.
An independent angiographic core laboratory analyzed all procedural angiograms and performed baseline and poststenting quantitative coronary angiographic measurements.
All routine hospital practice parameters were collected into a Web-based data management system coordinated and analyzed by an independent company (KIKA Medical, Paris, France). Clinical follow-up included documentation of adverse events, in particular death, MI, reinterventions, stent thrombosis, bleeding, cardiac medication regimen, and angina status. Laboratory results were performed according to routine practice. Follow-up was performed at 1 month, 6 months, and 12 months, and yearly up to 5 years.
All clinical end points were adjudicated by an independent clinical events committee. There was 100% monitoring online. In 30% of all patients on-site source data verification was achieved. Twelve-month follow-up was 97%, and 2-year follow-up was 95%.
The primary end point was target lesion failure at 12 months. Target lesion failure was defined as a composite of cardiac death, MI (Q wave and non-Q wave attributable to the target vessel), and clinically driven target lesion revascularization at 12 months after the procedure. MI was defined as creatine kinase >2 times the upper limit of the normal range and an increased level of creatine kinase-MB in the absence or presence of new pathologic Q waves on electrocardiogram for non–Q-wave or Q-wave MI, respectively. Target lesion revascularization was defined as any repeat PCI of the target lesion or bypass surgery of the target vessel performed for recurrent angina, ischemia, or diameter stenosis ≥70% by quantitative coronary angiography. Target vessel revascularization was defined as any clinically driven repeat PCI or bypass surgery of the entire target vessel.
The following end points were measured at 1 month, 6 and 12 months, and 2, 3, 4, and 5 years: (1) patient-oriented composite end point defined as any-cause mortality, any MI or any coronary revascularization; (2) major adverse cardiac events (MACE), a composite of cardiac death, any MI, and target vessel revascularization; (3) death and MI; (4) stent thrombosis (definite and probable according to the Academic Research Consortium definitions); (5) duration of dual antiplatelet therapy; (6) clinically driven target lesion revascularization; (7) clinically driven target vessel revascularization; and (8) total revascularization rate (clinically and nonclinically driven).
Binary variables are presented as frequencies and were compared using Cochran–Mantel-Haenszel test or Fisher’s exact test. Continuous variables are expressed as mean ± SD and were compared using 2-sample t tests. All tests were 2-sided. Kaplan–Meier estimates were generated, and comparisons of MACE events were made using log-rank test. Data analysis was performed by an independent statistical office (SBD Analytics, Bekkevoort, Belgium).
Results
The NOBORI-2 trial enrolled 3,067 consecutive patients in 125 centers from Europe, Asia, Africa, and New Zealand. Of these, 1,640 patients (53.4%) had ACS and they comprise the present study population. In the ACS cohort, 931 (57%) had troponin increase. ST-segment elevation MI occurred in 248 patients (15%) and non–ST-segment elevation MI in 329 (20%).
There were 1,268 men (77%) and 372 women (23%). Demographics of the study population stratified by gender are presented in Table 1 . Women were on average 5 years older and had a greater prevalence of hypertension and diabetes. Men had more previous myocardial revascularization procedures and more often were smokers. There was no difference in previous MI, peripheral vascular disease, or congestive heart failure.
| Variable | Men | Women | p Value ⁎ |
|---|---|---|---|
| (n = 1,268) | (n = 372) | ||
| Age (years), mean ± SD | 63.1 ± 11.8 | 67.8 ± 10.5 | <0.0001 |
| Smoker | |||
| Current | 393 (33.6%) | 83 (23.9%) | 0.0005 |
| Former | 429 (36.7%) | 44 (12.6%) | <0.0001 |
| Hypercholesterolemia † | 793 (65.6%) | 235 (65.5%) | 1 |
| Hypertension ‡ | 782 (63.2%) | 265 (72.0%) | 0.0018 |
| Diabetes mellitus | 330 (26.5%) | 132 (36.7%) | 0.0002 |
| Insulin | 70 (5.6%) | 37 (10.3%) | 0.0026 |
| Oral medication | 179 (14.4%) | 68 (18.9%) | 0.04 |
| Diet only | 54 (4.3%) | 16 (4.4%) | 0.88 |
| Diabetes mellitus with retinopathy, neuropathy, or nephropathy | 32 (2.6%) | 17 (5.0%) | 0.04 |
| Heart failure | 46 (3.8%) | 14 (4.1%) | 0.87 |
| Peripheral vascular disease | 84 (6.9%) | 18 (5.2%) | 0.32 |
| Previous percutaneous coronary intervention | 350 (28.0%) | 80 (21.9%) | 0.02 |
| Previous coronary bypass | 106 (8.5%) | 17 (4.6%) | 0.02 |
| Cerebrovascular disease | 58 (4.8%) | 15 (4.4%) | 0.89 |
| Renal disease | 3.80% (46/1,211) | 2.04% (7/343) | 0.13 |
| Previous myocardial infarction | 423 (34.5%) | 110 (30.2%) | 0.15 |
| ST-segment elevation myocardial infarction before procedure | 194 (15.3%) | 54 (14.5%) | 0.74 |
| Non–ST-segment elevation myocardial infarction before procedure | 252 (19.9%) | 77 (20.7%) | 0.71 |
| Evidence of myocardial infarction (increased enzymes) | 728 (57.4%) | 203 (54.6%) | 0.34 |
The radial approach was more frequent in men ( Table 2 ). Men had more coronary disease, more treated lesions, and more implanted stents. Lesion type, distribution, and location were similar according to gender. Left main coronary artery stenting occurred in 31 patients (1.9%).
| Variable | Men | Women | p Value |
|---|---|---|---|
| Arterial access site | |||
| Femoral access | 724 (58.0%) | 247 (66.8%) | 0.0025 |
| Radial access | 518 (41.5%) | 122 (33.0%) | 0.0036 |
| Number of narrowed coronary arteries, mean ± SD | 1.78 ± 0.76 | 1.64 ± 0.73 | 0.0014 |
| 1 | 542 (42.8%) | 192 (51.8%) | 0.0025 |
| 2 | 462 (36.7%) | 122 (32.9%) | 0.20 |
| ≥3 | 260 (20.5%) | 57 (15.4%) | 0.03 |
| Number of treated vessels | 1,253 | 363 | |
| Mean ± SD | 1.27 ± 0.52 | 1.21 ± 0.44 | 0.06 |
| Number of coronary arteries treated | |||
| 1 | 956 (75.4%) | 293 (78.8%) | 0.19 |
| 2 | 255 (20.1%) | 65 (17.5%) | 0.39 |
| ≥3 | 42 (3.3%) | 5 (1.3%) | 0.051 |
| Number of lesions treated | 1,902 | 507 | |
| Mean ± SD | 2.12 ± 1.16 | 1.88 ± 1.08 | 0.0002 |
| 1 | 483 (38.1%) | 176 (47.4%) | |
| 2 | 382 (30.2%) | 110 (29.7%) | |
| 3 | 231 (18.2%) | 51 (13.8%) | |
| 4 | 107 (8.5%) | 20 (5.4%) | |
| 5 | 64 (5.1%) | 14 (3.8%) | |
| Total number of implanted stents per patient | |||
| Mean ± SD | 1.80 ± 1.12 | 1.61 ± 1.07 | 0.0005 |
| 1 | 627 (49.5%) | 219 (58.9%) | |
| 2 | 370 (29.2%) | 82 (22.0%) | |
| 3 | 145 (11.4%) | 41 (11.0%) | |
| 4 | 56 (4.4%) | 12 (3.2%) | |
| 5 | 32 (2.5%) | 2 (0.5%) | |
| ≥6 | 15 (1.2%) | 5 (1.3%) | |
| Total implanted stents per lesion | |||
| Mean ± SD | 1.20 ± 0.56 | 1.18 ± 0.53 | 0.46 |
| Target vessel | |||
| Right coronary artery | 535 (28.1%) | 167 (32.9%) | 0.04 |
| Left anterior descending coronary artery | 783 (41.2%) | 215 (42.4%) | 0.61 |
| Left circumflex coronary artery | 515 (27.1%) | 160 (20.9%) | 0.0051 |
| Left main coronary artery | 26 (1.4%) | 5 (1.0%) | 0.66 |
| Saphenous vein graft | 43 (2.3%) | 14 (2.8%) | 0.51 |
| Dissection occurred | 79 (4.2%) | 28 (5.5%) | 0.18 |
| Procedural information | |||
| Predilatation performed | 1,354 (71.3%) | 361 (71.2%) | 1 |
| Postdilatation performed | 653 (34.5%) | 159 (31.4%) | 0.20 |
| Maximum stent deployment pressure | |||
| Mean ± SD (n) | 14.77 ± 3.51 | 14.27 ± 3.15 | 0.92 |
| Lesion characteristics | |||
| Ostial lesion | 170 (10.5%) | 46 (10.1%) | 0.86 |
| Aorto-ostial lesion | 46 (3.2%) | 19 (4.7%) | 0.17 |
| Eccentricity | 1,316 (81.4%) | 362 (79.4%) | 0.34 |
| Lesion angulation | 148 (9.2%) | 43 (9.4%) | 0.85 |
| Bifurcation | 352 (21.8%) | 57 (12.5%) | <0.0001 |
| Lesion ulceration | 165 (10.2%) | 37 (8.2%) | 0.21 |
| Lesion occlusion | 182 (11.5%) | 54 (12.0%) | 0.74 |
| Moderate to severe tortuosity | 123 (7.6%) | 37 (8.1%) | 0.69 |
| Moderate to severe calcification | 404 (25.0%) | 128 (28.1%) | 0.18 |
| (Possible) thrombus in lesion | 244 (15.1%) | 69 (15.1%) | 1 |
| Lesion type | |||
| A | 45 (2.8%) | 23 (5.1%) | 0.02 |
| B1 | 381 (23.6%) | 121 (26.6%) | 0.19 |
| B2 | 678 (41.9%) | 176 (38.7%) | 0.22 |
| C | 513 (31.7%) | 134 (29.5%) | 0.36 |
Quantitative coronary angiographic information is presented in Table 3 . Reference vessel size, minimal lumen diameter, and percent diameter stenosis at baseline and after DES implantation were similar.
| Men | Women | p Value | |
|---|---|---|---|
| Baseline | |||
| Reference vessel diameter | 2.62 ± 0.58 | 2.57 ± 0.52 | 0.27 |
| Minimal lumen diameter (mm) | 0.79 ± 0.48 | 0.76 ± 0.49 | 0.11 |
| Diameter stenosis | 69.7 ± 17.1 | 70.6 ± 17.5 | 0.19 |
| Lesion length | 15.87 ± 9.08 | 15.34 ± 9.25 | 0.14 |
| After pecutaneous coronary intervention | |||
| Reference vessel diameter | 2.89 ± 0.51 | 2.83 ± 0.48 | 0.66 |
| Minimal lumen diameter (mm) | 2.51 ± 0.48 | 2.47 ± 0.46 | 0.84 |
| Diameter stenosis | 13.29 ± 7.19 | 12.73 ± 7.67 | 0.47 |
| Quantitative coronary angiographic gain | 1.72 ± 0.59 | 1.70 ± 0.59 | 0.82 |
Table 4 presents in-hospital results. There was no difference in death, MI, or need for revascularization. Total in-hospital MACE did not differ according to gender (0.7% vs 1.1%, p = 0.51). Bleeding was similar. Length of stay was longer in women (4.3 ± 16.4 vs 3.2 ± 10.3, p = 0.054; Table 4 ).
| Variable | Men | Women | p Value |
|---|---|---|---|
| Index hospitalization duration (days after procedure), mean ± SD | 3.2 ± 10.1 | 4.3 ± 16.4 | 0.054 |
| Postprocedure increase of cardiac enzymes | |||
| Creatine kinase 2× upper limit | 19 (3.5%) | 3 (1.8%) | 0.32 |
| Creatine kinase-MB 3× upper limit | 0 (0%) | 1 (0.6%) | 0.24 |
| Troponin 5× upper limit | 3 (0.6%) | 0 (0%) | 1 |
| Adverse events in hospital (per patient) | |||
| Death | |||
| Cardiac death in hospital | 1 (0.2%) | 1 (0.3%) | 0.54 |
| Noncardiac death in hospital | 0 (0.0%) | 0 (0.0%) | |
| Myocardial infarction | |||
| Any myocardial infarction in hospital | 7 (0.6%) | 3 (0.8%) | 0.70 |
| Non–Q-wave myocardial infarction in hospital | 7 (0.6%) | 2 (0.5%) | 1 |
| Q-wave myocardial infarction in hospital | 0 (0.0%) | 1 (0.3%) | 0.23 |
| Target vessel myocardial infarction in-hospital | 6 (0.5%) | 3 (0.8%) | 0.43 |
| Periprocedural myocardial infarction | 5 (0.4%) | 2 (0.5%) | 0.66 |
| Revascularization | |||
| Any target vessel revascularization in hospital | 2 (0.2%) | 1 (0.3%) | 0.54 |
| Any target lesion revascularization in hospital | 2 (0.2%) | 1 (0.3%) | 0.54 |
| Composite end points | |||
| Major adverse cardiac events in hospital | 9 (0.7%) | 4 (1.1%) | 0.51 |
| Target lesion failure in-hospital | 8 (0.6%) | 4 (1.1%) | 0.49 |
| Cardiac death, any myocardial infarction in hospital | 9 (0.7%) | 4 (1.1%) | 0.51 |
| Bleeding | |||
| Any bleeding or vascular complications in hospital | 9 (0.7%) | 2 (0.5%) | 1 |
| Fatal bleeding in hospital | 0 (0.0%) | 0 (0.0%) | |
| Clinically overt bleeding with hemoglobin decrease >3 g/dl | 2 (0.2%) | 0 (0.0%) | 1 |
| Clinically overt bleeding requiring transfusion | 4 (0.3%) | 1 (0.3%) | 1 |
| Bleeding with hemodynamic compromise | 0 (0.0%) | 1 (0.3%) | 0.23 |
| Bleeding requiring intervention or decompression to stop or control the event | 1 (0.1%) | 0 (0.0%) | 1 |
| Retroperitoneal, intracranial, or intraocular bleeding | 2 (0.2%) | 0 (0.0%) | 1 |
There was a very high rate of follow-up of the participants in this study: 99% for 6 months, 97% for 1 year, and 95% for 2 years. Table 5 presents 1-, 6-, 12-, and 24-month follow-ups.
| Variable | 1 Month | 6 Months | 1 Year | 2 Years | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Men | Women | p Value | Men | Women | p Value | Men | Women | p Value | Men | Women | p Value | |
| Composite end points | ||||||||||||
| Major adverse cardiac events | 21 (1.7%) | 7 (1.9%) | 0.82 | 48 (3.8%) | 20 (5.4%) | 0.18 | 72 (5.7%) | 27 (7.3%) | 0.27 | 95 (7.5%) | 33 (8.9%) | 0.38 |
| Cardiac death | 7 (0.6%) | 3 (0.8%) | 0.70 | 12 (1.0%) | 6 (1.6%) | 0.27 | 17 (1.3%) | 10 (2.7%) | 0.10 | 25 (2.0%) | 12 (3.2%) | 0.16 |
| Any myocardial infarction | 14 (1.1%) | 6 (1.6%) | 0.42 | 19 (1.5%) | 10 (2.7%) | 0.18 | 26 (2.1%) | 12 (3.2%) | 0.24 | 32 (2.5%) | 13 (3.5%) | 0.37 |
| Target lesion failure | 18 (1.4%) | 7 (1.9%) | 0.48 | 39 (3.1%) | 16 (4.3%) | 0.25 | 57 (4.5%) | 22 (5.9%) | 0.27 | 72 (5.7%) | 27 (7.3%) | 0.27 |
| Cardiac death, any myocardial infarction | 20 (1.6%) | 7 (1.9%) | 0.65 | 29 (2.3%) | 14 (3.8%) | 0.14 | 40 (3.2%) | 18 (4.8%) | 0.15 | 51 (4.0%) | 21 (5.7%) | 0.19 |
| Target vessel revascularization | 8 (0.6%) | 4 (1.1%) | 0.49 | 29 (2.3%) | 14 (3.8%) | 0.14 | 47 (3.7%) | 18 (4.8%) | 0.36 | 66 (5.2%) | 22 (5.9%) | 0.60 |
| Anginal status | . | |||||||||||
| Stable angina | 103 (8.4%) | 27 (7.5%) | 0.66 | 78 (6.6%) | 31 (9.0%) | 0.12 | 90 (7.7%) | 3 (10.2%) | 0.142 | 88 (8.2%) | 24 (7.9%) | 0.91 |
| Unstable angina | 10 (0.8%) | 5 (1.4%) | 0.35 | 17 (1.4%) | 5 (1.5%) | 1 | 15 (1.3%) | 3 (0.9%) | 0.78 | 9 (0.8%) | 4 (1.3%) | 0.50 |
| Silent ischemia | 10 (0.8%) | 3 (0.8%) | 1 | 9 (0.7%) | 1 (0.3%) | 0.47 | 19 (1.6%) | 0.90% (3/332) | 0.44 | 22 (2.1%) | 4 (1.3%) | 0.48 |
| No angina | 1,100 (89.9%) | 324 (90.3%) | 0.92 | 1,080 (91.2%) | 307 (89.2%) | 0.29 | 1,046 (89.4%) | 292 (88.0%) | 0.48 | 949 (88.9%) | 272 (89.5%) | 0.84 |
| On dual antiplatelet therapy | 1,183 (98.1%) | 345 (98.6%) | 0.65 | 1,139 (96.6%) | 329 (97.3%) | 0.60 | 869 (74.5%) | 239 (72.9%) | 0.57 | 336 (31.7%) | 93 (30.8%) | 0.83 |
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