Outcomes in Contemporary Coronary Interventions with Drug-Eluting Stents for Acute Myocardial Infarction: The Gender Role

In a post hoc gender-based analysis of the TITAX-AMI trial,¹ Tuomainen et al noted that at 3-year follow-up, females had a higher trend of major adverse events than males for the composite endpoint of cardiac death, recurrent myocardial infarction (MI), and target lesion revascularization (TLR) (24.5% versus 16.3%; P=.059) driven mostly by a trend toward higher TLR. Multivariate analysis, however, showed that female gender per se was not a predictor of adverse events when adjusting for important demographic and angiographic variables. Females were older on presentation and with smaller coronary arteries, which are factors associated with higher adverse events. When these variables and others are adjusted for, predictors of adverse events were smaller stent diameter (P=.007), prior coronary bypass surgery (P=.007), and receiving the paclitaxel-eluting stent (PES) (P=.003) rather than gender. Similarly, data from a Polish registry² for acute ST-elevation myocardial infarction (STEMI) that included 8989 females and 17,046 males showed that women were older and had more risk factors. The incidence of in-hospital (11.9% vs 6.9%; P<.0001) and 12-month (22% vs 14.1%; P<.0001) mortality was significantly higher in women than men. In multivariate analysis, predictors of mortality were pulmonary edema, cardiogenic shock, cardiac arrest, age, diabetes, and anterior infarction. Gender was not an independent predictor of mortality. In addition, similar data were reported from the Korean Acute Myocardial Infarction Registry (KAMIR),³ which included 4037 patients admitted with STEMI to 41 facilities. In this registry, women had higher rates of in-hospital mortality (8.6% vs 3.2%; P<.01) and cardiac death (7.1% vs 2.8%; P<.01) than men. Multivariate analysis identified age, prior angina, hypertension, a higher Killip class, reduced LV systolic function, and a Thrombolysis in Myocardial Infarction flow grade <3 after angioplasty as predictors of in-hospital death. Female gender was also not an independent predictor of in-hospital mortality in this registry. Furthermore, recent data from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) PCI registry recently reported that differences in mortality between men and women no longer exist post PCI.⁴

In contrast to the above data, the mandatory Greater Paris Coronary Intervention Registry⁵ with 16,760 STEMI patients from 41 centers showed that female gender per se was an independent predictor of in-hospital mortality (9.8% vs 4.3%; P<.0001). This is also similar to published data on non-STEMI and unstable angina patients from the randomized RITA-3 trial.⁶ In this study, 1810 patients (682 women and 1128 men) were randomized to early intervention versus initial conservative treatment. More men than women benefited from an early intervention strategy with fewer deaths or non-fatal myocardial infarctions at 1 year.

In the TITAX-AMI trial,¹ males receiving the bioactive stent (BAS) had better outcomes than males or females receiving the PES, and females receiving the BAS had the same outcome as females receiving the PES stent. The BAS stent was also more effective in males than in females in reducing major adverse events. Also, Nakatani et al⁷ showed an interaction between female gender and reduced smooth muscle cell proliferation in patients treated with the zotarolimus-eluting stent (ZES). In their study, restenosis was significantly more reduced in women than men with ZES. In contrast, data from RESEARCH (Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital) and T-SEARCH (Taxus-Stent Evaluated at Rotterdam Cardiology Hospital)⁸ showed no interaction with the rapamycin and paclitaxel stents and gender. DES reduced revascularization equally in both men and women compared to bare-metal stents in these studies. Similarly, data from the SPIRIT II and SPIRIT III studies⁹ indicated that the everolimus-eluting stent was superior to the PES in reducing angiographic late loss, major adverse events and target vessel failure. There was no interaction between gender and stent type in reducing major adverse events at 2 years. Whether an interaction between stent type and gender exists needs to be confirmed in future studies. It is possible that if interaction between stent and gender exists, it is likely to be stent-specific.

In summary, when females present with an acute coronary syndrome (ACS), they are usually older, have more comorbidities, and are hemodynamically more unstable. In addition, they have smaller coronaries and tend to have less successful PCI. Despite our ability to statistically identify predictors of mortality in an ACS patient, these predictors remain inherently present more in women than men, which explains the worse outcomes in women irrespective of whether gender per se is or is not an independent predictor of adverse events post PCI. The TITAX-AMI confirms these observations and supports the presence of a stent-specific gender interaction.

References

1. Tuomainen PO, Ylitalo A, Niemelä M, et al. Gender-based analysis of the 3-year outcome of bioactive stents versus paclitaxel-eluting stents in patients with acute myocardial infarction: an insight from the TITAX-AMI trial. J Invasive Cardiol. 2012;24(3):104-108.
2. Sadowski M, Gasior M, Gierlotka M, et al. Gender-related differences in mortality after ST-segment elevation myocardial infarction: a large multicentre national registry. EuroIntervention. 2011;6(9):1068-1072. 
3. Park JS, Kim YJ, Shin DG, et al; for the Korean Acute Myocardial Infarction Registry (KAMIR) Group. Gender differences in clinical features and in-hospital outcomes in ST-segment elevation acute myocardial infarction: from the Korean Acute Myocardial Infarction Registry (KAMIR) study. Clin Cardiol. 2010;33(8):E1-E6.
4. Duvernoy CS, Smith DE, Manohar P, et al. Gender differences in adverse outcomes after contemporary percutaneous coronary intervention: an analysis from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) percutaneous coronary intervention registry. Am Heart J. 2010;159(4):677-683.
5. Benamer H, Tafflet M, Bataille S, et al; for the CARDIO-ARHIF Registry Investigators. Female gender is an independent predictor of in-hospital mortality after STEMI in the era of primary PCI: insights from the Greater Paris Area PCI Registry. Eurointervention. 2011;6(9):1073-1079.
6. Clayton TC, Pocock SJ, Henderson RA, et al. Do men benefit more than women from an interventional strategy in patients with unstable angina or non-ST elevation myocardial infarction? The impact of gender in the RITA 3 trial. Eur Heart J. 2004;25(18):1641-1650.
7. Nakatani D, Ako J, Tremmel JA, et al. Sex differences in neointimal hyperplasia following endeavor zotarolimus-eluting stent implantation. Am J Cardiol. 2011;108(7):912-917. 
8. Onuma Y, Kukreja N, Daemen J, et al; for the Interventional Cardiologists of Thoraxcenter. Impact of sex on 3-year outcome after percutaneous coronary intervention using bare-metal and drug-eluting stents in previously untreated coronary artery disease: insights from the RESEARCH (Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital) and T-SEARCH (Taxus-Stent Evaluated at Rotterdam Cardiology Hospital) Registries. JACC Cardiovasc Interv. 2009;2(7):603-610.
9. Seth A, Serruys PW, Lansky A, et al. A pooled gender based analysis comparing the XIENCE V(R) everolimus-eluting stent and the TAXUS paclitaxel-eluting stent in male and female patients with coronary artery disease, results of the SPIRIT II and SPIRIT III studies: two-year analysis. EuroIntervention. 2010;5(7):788-794.

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From the Midwest Cardiovascular Research Foundation, Davenport, Iowa.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Shammas has received Education and Research grants from Medtronic, Abbott, and Boston Scientific.
Address for correspondence: Nicolas W. Shammas, MD, MS, FACC, FSCAI, Research Director, Midwest Cardiovascular Research Foundation, 1622 East Lombard St., Davenport, IA 52803. Email: Shammas@mchsi.com