Gender Differences in Patients Treated with the Zotarolimus-Eluting Stent at a Tertiary Medical Center

Abstract: Background. Gender-related differences in long-term outcomes of patients receiving the Endeavor zotarolimus-eluting stent (ZES) (Medtronic) have not been well defined. In this study, we evaluate the differences between men (M) and women (W) for 2-year target vessel failure (TVF) in an unselected consecutive series of patients treated with the ZES at our institution. Methods. Data on 197 consecutive patients (133 M, 64 W) stented with the ZES were retrospectively analyzed. The primary endpoint of the study was to compare gender-related outcomes in TVF, defined as the combined endpoint of cardiac death, non-fatal myocardial infarction, and target vessel revascularization (TVR). Secondary endpoints included TLR, TVR, acute stent thrombosis (ST) as defined by the academic research consortium (ARC), and cardiac death. The cine angiograms of the first consecutive 122 patients (79 M, 43 W) were independently reviewed by a cardiologist blinded to clinical outcome and SYNTAX scoring was performed. Follow-up was achieved using medical records and/or phone calls and was censored at 730 days. Descriptive analysis was performed on all variables. Univariate analysis compared the M and W cohorts. Logistic regression analysis modeling for predictors of TVF was performed and survival analysis between the 2 groups was plotted. Results. The 2 groups were well matched for demographic, clinical, angiographic, and procedural variables. Angiographic complexity was also statistically similar between the 2 groups as judged by SYNTAX scoring (15.8 ± 10.9 M vs 13.5 ± 8.3 W; P=.197). At 2-year follow-up, TVF was 22.6% and 32.8% (P=0.684) with no statistical difference between TLR (18.1% M vs 12.8% W), TVR (21.8% M vs 32.8% W), cardiac death (2.3% M vs 6.3% W), and definite and probable stent thrombosis (2.26% M vs 3.13% W). Logistic regression analyses modeling for age, gender, New York Heart Association (NYHA) class, non-left main (LM) bifurcation lesions, ostial lesions, trifurcating LM, and pre-percutaneous coronary intervention (PCI) lesion severity showed that a higher NYHA class (odds ratio [OR], 2.68; P=.005), ostial lesions (OR, 5.68; P<.001), bifurcating non-LM lesions (OR, 2.74; P=.015), and trifurcating LM lesions (OR, 28.24; P<.001) predicted a higher TVF. Female gender (P=.086) and age (P=.09) were not independent predictors of TVF. Conclusion. In this cohort of patients receiving ZES, men and women had similar outcomes at 2-year follow-up consistent with recent reports in the current era of PCI. Complex coronary anatomy (ostial, non-LM bifurcations, and LM trifurcations) and advanced heart failure were stronger predictors of higher TVF than gender and age.

J INVASIVE CARDIOL 2012;24(6):256-260

Key words: coronary stent, drug-eluting stent, zotarolimus, outcome gender, target lesion revascularization, stent thrombosis

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Earlier data suggested that women (W) have more procedural complications and worse outcome than men (M) after percutaneous coronary intervention (PCI).^1,2 Differences in gender-related outcomes, however, have diminished over time³ and some data even suggest that female gender is a predictor of better long-term mortality than men with revascularization.⁴ With the advent of drug-eluting stent (DES) options, the data continue to suggest that differences in long-term outcomes between M and W after PCI are no longer present. Insights from the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) and Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) trials showed no differences in 3-year outcomes between M and W using the rapamycin and paclitaxel DESs.⁵ DESs reduced revascularization equally in both genders compared to bare-metal stents in these studies. Analysis from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) PCI registry recently reported that differences in mortality between M and W no longer exist post PCI.⁶

Long-term outcomes of M compared to W after PCI using the zotarolimus-eluting stent (ZES) remain unknown. In this study, we evaluate differences between M and W for target vessel failure (TVF) in an unselected consecutive series of patients treated with the ZES at our medical center with at least a 2-year follow-up completed.

Methods

Between June 1, 2008 and August 10, 2008, a total of 476 patients underwent PCI at our medical center. Of these, 249 patients underwent stenting with the ZES. All index lesions were included (de novo and restenotic). Patients were excluded if they had bypass graft stenting (n = 5), received a different type of stent than ZES during the same index procedure (n = 9), refused verbal consent required by the institutional review board (IRB) to obtain follow-up data via phone calls (n = 25), were lost to follow-up (n = 13), or were intolerant to platelet antagonists including aspirin, ticlopidine, or clopidogrel (n = 0). The remaining 197 patients were included in the final analysis. Retrospective data collection on ZES patients was approved by the IRB at our institution.

The study design is retrospective, with a 2-year follow-up using medical records, phone calls, or both from a single center. Patients were initially mailed a brief letter describing the protocol, followed by a phone call to obtain verbal consent to be part of the study (using an IRB-approved standardized script). All events reported by patients were verified by cross reference to medical records. Patients who refused to give consent were excluded from the database. Patients who expired had their death certificate retrieved when possible to evaluate the cause of their death. The duration of follow-up was limited to 2 years after the index procedure. The first 122 consecutive patients had their angiograms reviewed for angiographic and procedural variables by an interventional cardiologist blinded to patients’ outcomes. These consecutive patients underwent SYNTAX scoring to compare the angiographic complexity of M and W enrolled in the study.

Demographics and clinical variables collected included age, gender, prior PCI, previous myocardial infarction, family history of coronary artery disease, congestive heart failure classified by New York Heart Association (NYHA) class, renal insufficiency (creatinine ≥2 mg/dL), peripheral arterial disease, stroke, hypertension, hyperlipidemia, smoking history, diabetes mellitus, and clinical indication for index PCI procedure. Angiographic and procedural variables (n = 122) included SYNTAX scoring, number of stents used, reference vessel diameter, pre- and post-lesion severity, anti-coagulant and anti-platelet agents, and location of disease (bifurcating, trifurcating, left main, and ostial lesions).

The primary outcome of the study was TVF, defined as cardiac death, non-fatal myocardial infarction and target vessel revascularization (TVR). Secondary outcomes included TLR, TVR, acute stent thrombosis (ST) as defined by the Academic Research Consortium (ARC), and cardiac death. Patterns of restenosis in patients who underwent TLR were analyzed using the Mehran classification and are described in Table 3.⁷

Statistical analysis. Descriptive analysis was performed on all patients who were included in the study as well as on patients who had their angiograms reviewed independently. The cohort was then divided into 2 subgroups based on gender. T-testing was used for continuous variables and chi-square testing for dichotomous variables. Univariate analysis compared the demographic, clinical, angiographic, and outcome variables between the 2 groups. Multivariate modeling for TVF was performed adjusting for gender and age using logistic regression (LR) analysis. The LR analysis included gender, age, NYHA class, LM trifurcating and bifurcating disease, ostial lesions, non-LM bifurcations, and pre-PCI lesion severity. Survival analysis curve (Kaplan-Meier) was performed for TVF over the 2-year follow-up censored for death and follow-up duration to 730 days. Minitab software was used to conduct the analysis.

Results

Descriptive analysis on all patients is shown in Table 1. There was a high incidence of patients that had prior PCI (67.5%) and prior bypass surgery (21.8%). Two-thirds of the patients were current or prior smokers and 36.5% were diabetics. The majority of the patients were still on dual anti-platelet agents on follow-up. Patients were treated for unstable angina/non-ST elevation MI in 43.5%, staged procedure in 23.4%, angina with abnormal myocardial perfusion imaging (MPI) test in 17.7%, silent ischemia with abnormal MPI in 6.7%, ST-elevation MI in 4.8%, and ‘other’ in 3.8%. There were no statistical differences among any of the clinical and demographic variables between the M and W cohorts.

Angiographic variables are shown in Table 2. Notably, over 50% of patients had LM, ostial, and non-LM bifurcating lesions treated, reflecting a higher procedural complexity. Despite the complex disease treated, angiographic success, defined as obtaining a residual stenosis of less than 30%, was achieved in all cases. There was a relatively high number of stents placed per patient (2.8 ± 0.6), reflecting the longer lesion length treated. In fact, 44.6% of lesions were longer than 20 mm. In addition, in 29.3% of patients, the index lesions were restenotic. There were no statistical differences among any of the angiographic variables between M and W, including angiographic estimates of ejection fraction (Figure 1).

The pattern of restenosis among genders using ZES was also statistically similar. Using Mehran’s classification,⁷ occlusive and diffuse proliferative disease occurred in about one-third of patients, focal restenosis (<10 mm) in another one-third, and diffuse within the stent restenosis in the remaining one-third (Table 3, Figure 2).

Angiographic complexity was also statistically similar between the 2 groups as judged by SYNTAX scoring (15.8 ± 10.9 M vs 13.5 ± 8.3 W; P=.197). At 2 years of follow-up, TVF was 22.6% M and 32.8% W (P=.684; Figure 3) with no statistical difference between TLR (18.1% M vs 12.8% W), TVR (21.8% M vs 32.8% W), cardiac death (2.3% M vs 6.3% W), non-cardiac death (3% M vs 4.7%W), and definite and probable stent thrombosis (2.3% M vs 3.1% W). Logistic regression analyses (Table 4) modeling for age, gender, NYHA class, non-LM bifurcation lesions, ostial lesions, trifurcating LM, and pre-PCI lesion severity showed that a higher NYHA class (odds ratio [OR], 2.68; P=.005), ostial lesions (OR, 5.68; P<.001), bifurcating non-LM lesions (OR, 2.74; P=.015), and trifurcating LM lesions (OR, 28.24; P<.001) predicted a higher TVF. Female gender (P=.086) and age (P=.09) were not statistically independent predictors of TVF, but some interaction between these two variables was noted. A higher trend for TVF occurred in females at the age of 68, where peak TVF was noted, as compared to males at the same age (Figure 4). At the age of 68, men had a probability of 27.8% to have TVF, whereas females had a probability of 41%.

Discussion

Several older studies have suggested that women had higher complications and in-hospital mortality with PCI than men,^1,2 but a longitudinal trend toward improving outcome in females was noted.³ More recent data suggest that long-term major clinical events^8-12 and post-PCI mortality were not significantly different between men and women.⁶ In fact, in the BARI trial and after successful revascularization, female gender was even a stronger predictor of better outcome than men.⁴

The use of DESs in PCI has recently markedly increased and is now the dominant strategy used by interventionists. DESs significantly reduce repeat PCI procedures compared to BMSs. The RESEARCH and T-SEARCH trials showed no differences in 3-year outcomes between M and W using the rapamycin and paclitaxel DESs, which is consistent with recent data showing no gender-related differences in outcomes after PCI.⁵ Our data also support the lack of sex-related differences in 2-year outcomes after PCI using ZES. However, a higher rate of TVF is seen in both men and women in our study compared to a large ZES registry,¹³ probably related to a higher complexity of disease, including bifurcating and trifurcating LM, ostial and non-LM bifurcating lesions.

More males have proliferative and occlusive disease on follow-up than females (40% vs 21.4%, respectively) (Table 3 and Figure 4). This is consistent with published data showing that females have lower neointimal obstruction than males with the ZES.¹⁴ Diffuse in-stent restenosis, however, is more prevalent in the ZES than other DESs.^15,16

In this study, non-LM bifurcation disease, ostial lesions, and LM bifurcating and trifurcating disease were all associated with a higher TVF rate. This is consistent with the off-label use of DESs in these lesion subsets where higher TLR and event rates were reported.^17,18 When adjusting for these complex angiographic variables, gender was not a strong predictor of TVF.

Study limitations. The study is relatively small, but the 2 groups are strikingly statistically similar for demographic, clinical, angiographic, and procedural variables, allowing a meaningful comparison of outcomes between males and females. Also, the data appear to be consistent with recently published data with other DESs and show that ZES behaves similarly in both genders. This study is retrospective, but with good long-term follow-up, and the scoring of disease complexity was done independently by an operator blinded to clinical outcomes. Analysis of gender-related differences in outcomes from larger ZES registries is warranted to confirm these findings.

References

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15. Jensen LO, Maeng M, Thayssen P, et al. Late lumen loss and intimal hyperplasia after sirolimus-eluting and zotarolimus-eluting stent implantation in diabetic patients: the diabetes and drug-eluting stent (DiabeDES III) angiography and intravascular ultrasound trial. EuroIntervention. 2011;7(3):323-331.
16. Waseda K, Miyazawa A, Ako J, et al; ENDEAVOR IV trial investigators. Intravascular ultrasound results from the ENDEAVOR IV trial: randomized comparison between zotarolimus- and paclitaxel-eluting stents in patients with coronary artery disease. JACC Cardiovasc Interv. 2009;2(8):779-784.
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From the ¹Midwest Cardiovascular Research Foundation, Davenport, Iowa, and ²Genesis Health System, Davenport, Iowa.
Funding: The Midwest Cardiovascular Research Foundation (MCRF) has received research and educational grants from Medtronic. Supported in part by the Nicolas and Gail Research Fund at MCRF.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Lemke is a consultant for Genesis Health System. The authors report no conflicts of interest regarding the content herein.
Presented in part in abstract form at The Cardiovascular Research Technologies 2011, Washington DC.
Manuscript submitted January 16, 2012, provisional acceptance given January 30, 2012, final version accepted February 7, 2012.
Address for correspondence: Nicolas W. Shammas, MD, MS, FACC, FSCAI, Research Director, Midwest Cardiovascular Research Foundation, 1236 E Rusholme, Suite 300, Davenport, IA 52803. Email: Shammas@mchsi.com