Women Have Less Neointimal Hyperplasia Than Men With ZES
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Women are at decreased risk compared with men for neointimal hyperplasia when undergoing stent implantation with zotarolimus-eluting stents (ZES), according to a study published online July 25, 2011, ahead of print in the American Journal of Cardiology. In addition, study results indicated that women also develop less binary restenosis at 8 months than their male counterparts receiving ZES.
In the study, researchers led by Peter J. Fitzgerald, MD, PhD, of Stanford University (Stanford, CA), compared sex differences in neointimal proliferation in a group of patients implanted with an Endeavor ZES (Medtronic CardioVascular, Santa Rosa, CA) vs. a bare-metal stent (BMS). Data on 476 patients were obtained from the IVUS database of the Cardiovascular Core Analysis Laboratory at Stanford.
Baseline IVUS measurements in the ZES group showed that women had a significantly smaller vessel volume index, plaque volume index, luminal volume index and minimum luminal area compared with men. Similar non-significant trends were also seen in the BMS group.
Clear Gender Differences for ZES, BMS
At 8 months, a significant association was shown between female sex and stent type for both neointimal obstruction (P = 0.001) and maximum cross-sectional narrowing (CSN; P = 0.003). Interestingly, although women had better outcomes than men for neointimal obstruction and CSN with ZES, the opposite was true for women who received BMS (tables 1 and 2).
Table 1. Gender Differences for ZES at 8 Months
|
Women |
Men |
P Value |
Neointimal Obstruction |
15.5 ± 9.5% |
18.2 ± 10.9% |
0.025 |
Max. CSN |
30.3 ± 13.2% |
34.8 ± 15.0% |
0.007 |
Table 2. Gender Differences for BMS at 8 Months
|
Women |
Men |
P Value |
Neointimal Obstruction |
36.3 ± 15.9% |
27.5 ±17.2% |
0.053 |
Max. CSN |
54.3 ± 18.6% |
45.6 ± 18.3% |
0.080 |
After adjusting for clinical and angiographic baseline characteristic differences, female sex remained independently associated with improved outcomes for both neointimal obstruction (P = 0.027) and maximum CSN (P = 0.004) in patients receiving ZES.
At 8 months, ZES demonstrated a significantly lower incidence of binary restenosis compared with BMS for both men (8.9% vs. 26.2%; P < 0.001) and women (1.9% vs. 41.2%; P < 0.001), an independent association later confirmed by multivariate linear regression analysis. However, the magnitude of the risk reduction was significantly greater for women in the ZES group compared with men (P = 0.015).
Findings Do Not Extend to All DES
In general, studies comparing sex differences have shown that the extent of benefit for women and men is similar for DES, according to David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA).
But “here we see a study where the magnitude of benefit seems to be greater for women,” Dr. Kandzari said in a telephone interview with TCTMD. “So these findings, at least to date, are not generalizable to other DES. This seems to be a unique finding with the Endeavor stent.”
Dr. Kandzari and colleagues observed a similar trend for women with ZES in a larger study looking at data from 2,132 patients, including 608 women (Brown RA, Catheter Cardiovasc Interv. 2010;76:804-813). Although long-term safety and efficacy outcomes were similar among all patients treated with ZES, and despite the fact that women had greater baseline risk, women given ZES showed a larger reduction in angiographic restenosis and repeat revascularization than men.
However, because both that study and the current one are observational in nature, applying these findings broadly across clinical practice would require a larger, randomized trial, he added.
Explanation for Sex Differences May Be Multifactorial
Dr. Fitzgerald and colleagues proposed several possible reasons for the sex-differences seen with ZES. The first is that in the current and previous studies, despite patients being enrolled consecutively, the percentage of female patients varied between trials, they wrote. In addition, a lack of secondary preventive measures, “with women less likely than men to receive optimal medical therapy” may have affected the results. Finally, the data may have been skewed due to a tendency for women to be treated with medical therapy rather than repeat revascularization after a procedure.
“There are no direct answers for why women may be faring better than men,” Dr. Kandzari commented.
Although there has been a history of potential differences in outcomes in women compared with men in interventional cardiology, generally suggesting that women have higher rates of periprocedural MI, repeat revascularization, and procedural complications, the experience with ZES has not reflected that, Dr. Kandzari said.
“There have also been studies suggesting that women have greater micro- and macrovascular dysfunction, that they have more diffuse atherosclerosis…[and] altered platelet reactivity, and higher levels of inflammatory markers compared with men. But again, we have not seen that here,” Dr. Kandzari said.
“To invoke a biological mechanism of hormonal differences or altered vascular response in women compared with men would be strictly hypothetical,” he added. “It is beyond what we know about vascular biology within interventional cardiology at present.”
Greater Understanding Needed
Moving forward, interventional cardiologists should expect to see a greater emphasis in trials on better understanding of cardiovascular outcomes in women, and in women vs. men, Dr. Kandzari said.
“These studies are the start of what we will be seeing in future clinical trials now that examining sex differences is one of the 5 key objectives put forth by the FDA for this year,” Dr. Kandzari said.
The real question, he noted, will be discovering if there are truly biologically based sex differences in response to drugs or device therapy, or if these findings are simply chance or observational findings.
Study Details
The database included patients enrolled in ENDEAVOR II, ENDEAVOR II Continued Access Registry, ENDEAVOR III and ENDEAVOR IV who had ZES implanted and also had volumetric IVUS analysis available at 8 months. Data from control patients who were implanted with BMS were taken only from ENDEAVOR II and included 8-month volumetric IVUS analysis.
According to baseline data, women in the ZES group were older and more likely to have hypertension, diabetes and a family history of coronary heart disease compared with men; however, they were less likely to have a history of MI and PCI. Women also had significantly smaller preprocedural reference diameters than men.
Sources:
1. Nakatani D, Ako J, Tremmel JA, et al. Sex differences in neointimal hyperplasia following Endeavor zotarolimus-eluting stent implantation. Am J Cardiol. 2011;Epub ahead of print.
2. Brown RA, Williams M, Barker CM, et al. Sex-specific outcomes following revascularization with zotarolimus-eluting stents: Comparison of angiographic and late-term clinical results. Catheter Cardiovasc Interv. 2010;76:804-813.
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Disclosures
- Dr. Fitzgerald reports serving as a consultant for Medtronic.
- Dr. Kandzari reports receiving research, grant support and consulting honoraria from Abbott Vascular and Medtronic.
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