Inconsistent results in outcomes have been observed between the genders after drug-eluting stent implantation. The aim of this study was to investigate gender differences in neointimal proliferation for the Endeavor zotarolimus-eluting stent (ZES) and the Driver bare-metal stent (BMS). A total of 476 (n = 391 ZES, n = 85 BMS) patients whose volumetric intravascular ultrasound analyses were available at 8-month follow-up were studied. At 8 months, neointimal obstruction and maximum cross-sectional narrowing (CSN) were significantly lower in women than in men receiving ZES (neointimal obstruction 15.5 ± 9.5% vs 18.2 ± 10.9%, p = 0.025; maximum CSN 30.3 ± 13.2% vs 34.8 ± 15.0%, p = 0.007). Conversely, these parameters tended to be higher in women than in men receiving BMS (neointimal obstruction 36.3 ± 15.9% vs 27.5 ± 17.2%, p = 0.053; maximum CSN 54.3 ± 18.6% vs 45.6 ± 18.3%, p = 0.080). There was a significant interaction between stent type and gender regarding neointimal obstruction (p = 0.001) and maximum CSN (p = 0.003). Multivariate linear regression analysis revealed that female gender was independently associated with lower neointimal obstruction (p = 0.027) and maximum CSN (p = 0.004) for ZES but not for BMS. Compared to BMS, ZES were independently associated with a reduced risk for binary restenosis in both genders (odds ratio for women 0.003, p = 0.001; odds ratio for men 0.191, p <0.001), but the magnitude of this risk reduction with ZES was significantly greater in women than men (p = 0.015). In conclusion, female gender is independently associated with decreased neointimal hyperplasia in patients treated with ZES. The magnitude of risk reduction for binary restenosis with ZES is significantly greater in women than in men.
The degree to which gender affects outcomes after percutaneous coronary intervention is still controversial. In patients treated with balloon angioplasty or bare-metal stents (BMS), inconclusive results have been obtained. In patients treated with first-generation drug-eluting stents, including sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES), the risk for target lesion revascularization was similar between women and men after adjustment for clinical characteristics. However, in a pooled analysis of the Endeavor (Medtronic CardioVascular, Inc., Santa Rosa, California) zotarolimus-eluting stent (ZES) trials (ENDEAVOR I, ENDEAVOR II, ENDEAVOR II Continued Access Registry, and ENDEAVOR III), men had a 1.79-fold higher risk for target lesion revascularization than women by multivariate analysis. To further elucidate this suggested gender difference, we compared vessel responses after ZES and BMS implantation in women and men using detailed intravascular ultrasound (IVUS) analysis.
Methods
The Endeavor ZES system is composed of the cobalt-chromium alloy Driver (Medtronic, Inc., Minneapolis, Minnesota) BMS, with a phosphorylcholine polymer that elutes zotarolimus. A dose concentration of 10 μg zotarolimus per 1 mm stent length, with 98% of zotarolimus elution within 14 days, provides treatment-level doses in the tissue for about 28 days after implantation. Several pivotal clinical trials evaluating the efficacy and safety of the ZES have been conducted. ENDEAVOR II, including the ENDEAVOR II Continued Access Registry, was a trial examining the safety and efficacy of ZES. ENDEAVOR III and ENDEAVOR IV were also randomized trials comparing ZES with SES and PES, respectively. These trials used similar major inclusion and exclusion criteria as well as planned IVUS interrogation for all patients at prespecified enrollment sites after the procedure and at follow-up. The results of these trials have been described elsewhere.
Data were obtained from the IVUS database of the Cardiovascular Core Analysis Laboratory at Stanford University (Stanford, California). Patients enrolled in ENDEAVOR II, ENDEAVOR II Continued Access Registry, ENDEAVOR III, and ENDEAVOR IV who were treated with ZES and had volumetric IVUS analysis available at 8-month follow-up were identified for study inclusion. Similarly, control subjects were patients in the ENDEAVOR II trial who were treated with the Driver BMS and had volumetric IVUS analysis available at 8-month follow-up. There were no significant differences in baseline demographic and angiographic parameters before procedure between the IVUS and total cohorts. The protocol was approved by the institutional review board and written informed consent was obtained from each patient.
IVUS was performed in a standard fashion using an automated, motorized 0.5 mm/second pullback with a commercially available imaging system (40-MHz IVUS catheter, Boston Scientific Corporation, Natick, Massachusetts; or 20-MHz IVUS catheter, Volcano Corporation, Rancho Cordova, California) at baseline and 8-month follow-up. IVUS analysis was conducted in an independent core laboratory at Stanford University Medical Center (Cardiovascular Core Analysis Laboratory), and investigators were blinded to patient characteristics and randomization assignments. Volumetric measurements were performed using software (echoPlaque; Indec Systems, Inc., Santa Clara, California), as previously described. Volume index (volume [mm 3 ]/length [mm]) was calculated for the vessel, plaque, neointima, stent, and lumen. Neointimal volume was then calculated as stent volume minus luminal volume, and neointimal obstruction was calculated as neointimal volume divided by stent volume (percent). Cross-sectional narrowing (CSN; percent) was defined as neointimal area divided by stent area. Incomplete stent apposition at baseline was defined as ≥1 stent strut clearly separated from the vessel wall with evidence of blood speckles behind the strut in a vessel segment not associated with any side branches.
Categorical variables are expressed as frequency (percentage) and were compared using chi-square tests or Fisher’s exact tests. Continuous variables are reported as mean ± SD and were compared using unpaired Student’s t tests. Multiple linear regression analysis was used to determine the correlation of female gender with neointimal obstruction and maximum CSN. Multivariate logistic regression analysis was also performed to determine whether ZES were independently associated with a reduced risk for binary restenosis, defined as >50% diameter stenosis on angiography at 8-month follow-up. Variables with p values <0.20 on univariate analyses for ZES between the genders were inserted into these multivariate models after screening for multicollinearity. Variables inserted into these models were age, hypertension, diabetes mellitus, hyperlipidemia, family history, history of myocardial infarction, previous percutaneous coronary intervention, type B2 or C lesion, and minimum lumen area at baseline. All tests were 2 sided, and statistical significance was defined as p <0.05. All analyses were performed using PASW Statistics version 18 (SPSS, Inc., Chicago, Illinois).
Results
We identified 391 patients with ZES and 85 patients with BMS meeting the inclusion criteria. The baseline clinical, angiographic, and procedural characteristics, stratified by gender and stent type, are listed in Tables 1 and 2 . In the ZES group, women were significantly older and more likely to have hypertension, diabetes mellitus, and family histories of coronary heart disease but less likely to have histories of myocardial infarction and percutaneous coronary intervention compared to men. Similar trends were seen in the BMS group ( Table 1 ). Angiographically, women had significantly smaller preprocedural reference diameters than men, regardless of stent type. Otherwise, there were no significant differences in lesion location, lesion type, or lesion length between women and men in either group ( Table 2 ).
| Variable | ZES | BMS | ||||
|---|---|---|---|---|---|---|
| Women (n = 110) | Men (n = 281) | p Value | Women (n = 18) | Men (n = 67) | p Value | |
| Age (years) | 64.4 ± 9.5 | 59.3 ± 10.7 | <0.001 | 61.2 ± 8.8 | 58.5 ± 10.8 | 0.336 |
| Hypertension | 81.8% | 65.6% | 0.002 | 77.8% | 54.5% | 0.075 |
| Diabetes mellitus | 30.9% | 19.9% | 0.020 | 22.2% | 11.9% | 0.266 |
| Hyperlipidemia | 88.2% | 82.5% | 0.167 | 83.3% | 82.1% | 0.902 |
| Current smoker | 23.4% | 25.3% | 0.698 | 27.8% | 29.9% | 0.864 |
| Family history | 51.8% | 41.5% | 0.101 | 60.0% | 32.3% | 0.047 |
| Previous myocardial infarction | 19.3% | 28.3% | 0.067 | 27.8% | 50.7% | 0.083 |
| Previous percutaneous coronary intervention | 16.4% | 24.9% | 0.069 | 11.1% | 19.7% | 0.399 |
| Variable | ZES | BMS | ||||
|---|---|---|---|---|---|---|
| Women (n = 110) | Men (n = 281) | p Value | Women (n = 18) | Men (n = 67) | p Value | |
| Target coronary artery | 0.534 | 0.734 | ||||
| Right coronary artery | 24.5% | 23.8% | 33.3% | 31.3% | ||
| Left anterior descending | 35.5% | 37.4% | 50.0% | 43.3% | ||
| Left circumflex | 15.5% | 19.9% | 16.7% | 25.4% | ||
| Type of coronary lesion | 0.668 | 0.311 | ||||
| A | 5.5% | 4.3% | 5.6% | 3.0% | ||
| B1 | 29.1% | 23.2% | 22.2% | 18.2% | ||
| B2 | 40.9% | 46.8% | 27.8% | 54.5% | ||
| C | 24.5% | 25.7% | 44.4% | 24.2% | ||
| B2/C | 65.5% | 72.5% | 0.170 | 72.2% | 78.8% | 0.555 |
| Pre–reference diameter (mm) | 2.66 ± 0.40 | 2.77 ± 0.46 | 0.028 | 2.62 ± 0.34 | 2.91 ± 0.5 | 0.024 |
| Pre–lesion length (mm) | 13.99 ± 5.33 | 14.83 ± 6.05 | 0.202 | 14.59 ± 6.76 | 14.74 ± 5.39 | 0.924 |
| Stent diameter (mm) | 3.05 ± 0.33 | 3.11 ± 0.36 | 0.029 | 2.99 ± 0.33 | 3.19 ± 0.33 | 0.139 |
| Total stent length (mm) | 23.2 ± 7.4 | 23.0 ± 6.6 | 0.809 | 23.8 ± 5.1 | 22.9 ± 6.7 | 0.593 |
At baseline, IVUS measurements in the ZES group, including vessel volume index, plaque volume index, luminal volume index, and minimum luminal area, were significantly smaller in women than men ( Table 3 ). Similar trends were seen in the BMS group, although they were not statistically different. At 8 months, neointimal obstruction and maximum CSN were significantly lower in women compared to men receiving ZES (p = 0.025 and p = 0.007, respectively). Conversely, with BMS, these parameters tended to be higher in women than men (neointimal obstruction p = 0.053, maximum CSN p = 0.080). There was a significant interaction between gender and stent type in terms of neointimal obstruction (p = 0.001) and maximum CSN (p = 0.003). Likewise, the magnitude of change from follow-up to baseline in lumen volume index was significantly lower in women than men with ZES (p = 0.002), while it was higher in women than men with BMS (p <0.001) (p for interaction = 0.051). After adjusting for clinical and angiographic differences in baseline characteristics, female gender was independently associated with a lower neointimal obstruction (p = 0.027) and maximum CSN (p = 0.004) in the ZES group but not in the BMS group ( Table 4 ).
| Variable | ZES | BMS | p Value for Interaction | ||||
|---|---|---|---|---|---|---|---|
| Women | Men | p Value | Women | Men | p Value | ||
| Baseline | |||||||
| Vessel VI (mm 3 /mm) | 12.5 ± 3.3 | 14.6 ± 4.3 | 0.001 | 13.9 ± 3.1 | 15.7 ± 4.2 | 0.232 | |
| Plaque VI (mm 3 /mm) | 5.7 ± 1.9 | 7.3 ± 2.7 | <0.001 | 6.1 ± 2.0 | 7.7 ± 2.7 | 0.093 | |
| Lumen VI (mm 3 /mm) | 6.7 ± 1.9 | 7.4 ± 2.0 | 0.020 | 7.3 ± 1.9 | 8.1 ± 2.2 | 0.232 | |
| Stent VI (mm 3 /mm) | 6.7 ± 1.9 | 7.4 ± 2.0 | 0.017 | 7.4 ± 1.9 | 8.2 ± 2.2 | 0.235 | |
| Minimum lumen area (mm 2 ) | 5.7 ± 1.7 | 6.1 ± 1.8 | 0.040 | 5.9 ± 1.6 | 6.8 ± 2.0 | 0.082 | |
| Stent expansion ratio ⁎ | 0.93 ± 0.15 | 0.95 ± 0.14 | 0.221 | 0.99 ± 0.16 | 0.96 ± 0.17 | 0.618 | |
| Incomplete stent apposition | 11.6% | 19.3% | 0.091 | 31.3% | 17.7% | 0.233 | |
| Follow-up | |||||||
| Vessel VI (mm 3 /mm) | 12.9 ± 3.2 | 14.8 ± 4.2 | <0.001 | 13.3 ± 3.5 | 15.8 ± 4.2 | 0.042 | |
| Plaque VI (mm 3 /mm) | 6.1 ± 1.8 | 7.8 ± 2.5 | <0.001 | 6.0 ± 2.0 | 8.1 ± 2.8 | 0.013 | |
| Lumen VI (mm 3 /mm) | 5.8 ± 1.7 | 6.0 ± 1.8 | 0.415 | 4.3 ± 1.0 | 5.6 ± 2.0 | <0.001 | |
| Minimum lumen area (mm 2 ) | 4.7 ± 1.6 | 4.6 ± 1.7 | 0.884 | 3.0 ± 1.1 | 4.0 ± 1.8 | 0.024 | |
| Neointimal obstruction (%) | 15.5 ± 9.5 | 18.2 ± 10.9 | 0.025 | 36.3 ± 15.9 | 27.5 ± 17.2 | 0.053 | 0.001 |
| Maximum CSN (%) | 30.3 ± 13.2 | 34.8 ± 15.0 | 0.007 | 54.3 ± 18.6 | 45.6 ± 18.3 | 0.080 | 0.003 |
| Incidence of maximum CSN ≥60% | 1.8% | 7.5% | 0.032 | 33.3% | 20.9% | 0.269 | 0.026 |
| Delta (follow-up minus baseline) | |||||||
| Vessel VI (mm 3 /mm) | 0.2 ± 0.9 | 0.1 ± 1.1 | 0.365 | 0.3 ± 0.8 | 0.2 ± 1.2 | 0.042 | 0.384 |
| Plaque VI (mm 3 /mm) | 0.1 ± 0.6 | 0.1 ± 1.0 | 0.983 | 0.3 ± 0.8 | 0.2 ± 0.8 | 0.013 | 0.365 |
| Lumen VI (mm 3 /mm) | −0.9 ± 1.0 | −1.4 ± 1.1 | 0.002 | −3.0 ± 1.7 | −2.4 ± 2.0 | <0.001 | 0.051 |
| Minimum lumen area (mm 2 ) | −1.0 ± 1.1 | −1.5 ± 1.2 | 0.002 | −2.8 ± 1.9 | −2.7 ± 1.8 | 0.833 | 0.023 |
⁎ Defined as stent VI divided by manufacture’s expected stent area.
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