Is PCI Harmful in Women? Insights in a Mixed Literature

It has been postulated that women have higher adverse events with percutaneous coronary intervention (PCI) when compared with men, but as PCI has improved, it also appears this has been reduced or eliminated. In this issue of the Journal, authors Movahed et al1 examine a very large, broad cohort of women and men undergoing PCI for all indications and disturbingly find that age-adjusted mortality has been, and remains, significantly higher in women than in men. The study examined patients from 1988 to 2004 in the Nationwide Inpatient Sample, the largest all-payer inpatient care database, containing data from approximately 8 million hospital stays each year in the U.S., with 38 states participating. They found that after a period of stable in-hospital mortality rates, mortality began to decline steadily after 1995. While rates declined in both women and men, the age-adjusted mortality rates in women were persistently higher than those of men. This finding of persistent, significantly higher rates of in-hospital mortality in women undergoing PCI is a concerning one and highlights several important questions in women with coronary artery disease (CAD). Historically, studies investigating the management of both stable CAD and acute coronary syndromes (ACS) have not included a large number of women, making the optimal management of women with cardiovascular disease, including the role of PCI, unclear. In fact, for a variety of reasons, women still consistently less often undergo PCI than men, with only 33% of all PCIs performed on women.² Still, the available literature may help us discern the significance of the present study and understand whether mortality in women presenting with CAD is higher than in men, and if this can be explained by comorbidities and other gender-inherent characteristics, and whether PCI itself affords either a differential benefit or, conversely, harm in women. Numerous investigations have revealed that women with non-ST-elevation ACS (NSTACS) fare as well as, or even better than men with respect to mortality. In contrast, multiple studies consistently have shown that the unadjusted mortality rate for women is up to two times higher than that of men when presenting with ST-elevation myocardial infarction (STEMI).^3–7 Many factors may help to explain the increase in mortality in women with myocardial infarction (MI). Women are older upon presentation and have higher rates of diabetes mellitus, hypertension and concomitant congestive heart failure.^3–6 In addition, rates of cardiogenic shock, despite a lower prevalence of multivessel disease, are higher in women on presentation. In most cases, these factors have mitigated, though not completely eliminated, the increased hazard of death with MI in women. The less frequent use of beneficial therapies has also been investigated as a reason for poorer outcomes in women with MI. One analysis found mortality was greater for women than men, but women had a lower likelihood of receiving interventions including PCI and coronary artery bypass grafting.⁸ When adjusting for differences in clinical characteristics rather than therapies received, mortality differences were lower, though persistent, potentially implicating the lack of these therapies in poorer outcome. Disparities in medication use in women have been demonstrated in numerous MI studies, including the early GUSTO-I trial, in which there was lower use of beta-blocking drugs and aspirin in women.⁶ Women seek medical attention later in the course of symptoms, and an earlier study of care in 1994 found that women not only had greater delay in seeking care, but also greater delays in receiving primary PCI and intensive care unit admission with MI.⁹ Thus, both gender inherent factors and differences in systems of care account for a significant portion of the difference in mortality between women and men. The fact that many studies still show persistent hazard despite adjustment for these factors, may suggest that other poorly studied biologic differences are also present. The observation of poorer outcomes in subgroups of women undergoing PCI raises the question of whether PCI itself is more harmful in women than in men. In this regard, PCI has been shown to result in higher rates of vascular complication and bleeding in women.¹⁰ In fact, historically higher complication rates in women have likely led many physicians to withhold PCI in women, though an examination of the literature shows in many cases this is not justified. For instance, in patients with NSTACS, modern randomized trials showed invasive management to be superior to conservative strategies. However, in women, the results of these same trials have been conflicting.¹² The TACTICS-TIMI 18 trial, in which invasive and conservative strategies were designed to reflect largely U.S.-based practice, did find that women benefit from invasive management, though closer examination reveals an underlying risk for adverse cardiovascular events was much more important in determining the benefit of PCI in women. The high-risk subset of women, characterized by elevated serum levels of troponin T, who underwent early invasive care had a significantly decreased rate of death, MI or recurrent ACS requiring hospitalization at 6 months (reduction of 44% with invasive care), whereas those at low risk, appeared to have no benefit, in part because of the increased bleeding and vascular complications, with little ischemic benefit. Another analysis of biomarker-defined risk similarly found that while women with a biomarker elevation fared better with invasive care, women without any biomarkers did well with conservative management. More disturbingly, when the subgroup of low-risk women received invasive therapy, their rate of death, MI, or recurrent ACS was tripled.¹² Thus, the present level of evidence supports the benefit and use of invasive therapy, including PCI in women who present with ACS and high-risk features. In contrast, primary PCI has been shown to be a superior therapy over fibrinolysis as a treatment for STEMI. In fact, in one observational trial in which revascularization rates by PCI were very high in both women and men, no difference in mortality rates by gender was demonstrated.¹⁴ In addition, in the small randomized study of 104 patients in the Primary Angioplasty for Myocardial Infarction trial, the use of primary angioplasty eliminated the difference in mortality observed between women and men who received fibrinolysis.¹⁵ Women had a mortality rate of 4% with primary angioplasty, which was comparable to that of men, and contrasted with a 14% mortality rate in women who received fibrinolysis. Thus, primary PCI for women with acute MI may represent a means of reducing the disparity in adverse outcomes after MI in women compared with men. The role of PCI versus medical therapy for stable CAD has not been thoroughly investigated specifically in women. However, registries which include stable angina patients suggest improved outcomes with PCI over time. In an analysis of the NHLBI Dynamic Registry, when compared to two previous registries from 1985–1986 and 1993–1994, more women in 1997–1998 had a significant degree of comorbidity than previously, yet their 1-year risk of mortality was similar, potentially reflecting the advances in outcomes in women undergoing PCI over time.¹⁰ In summary, mortality rates in women with CAD versus men vary depending upon presentation with angina versus infarction and can be explained in large part by a combination of both inherent differences in characteristics, and differences in beneficial therapies received. PCI does appear to pose an increased hazard of bleeding complications in women, though those women with the highest risk of ischemic complications, such as STEMI, benefit more from PCI than alternative medical therapies. With this in mind, reexamination of the analysis of Movahed et al helps to understand its significance. For one, though mortality was higher, the proportion of patients undergoing PCI for ACS is not reported. Beyond age, comorbidities and medical therapies received also unfortunately cannot be known in the present study. Finally, although it is concerning that age-adjusted mortality is higher in women, the fact that mortality has decreased in both women and men potentially suggests that PCI is not mediating the poorer outcomes in women. It also, unfortunately, suggests that PCI is not able to fully “close the gap” that remains between women and men requiring treatment for obstructive CAD. Indeed, a preliminary analysis of the modern APEX Acute MI trial suggests that women with infarction have similar mortality to men in the setting of primary PCI, but only after accounting for differences in characteristics and care.¹⁵ In this regard, further investigation is needed for therapies and advances in PCI from which women may particularly benefit. Newer agents such as direct thrombin inhibitors like bivalirudin and thienopyridines may benefit women more so than men by reducing bleeding and vascular complications. Drug-eluting stents also may have particular long-term benefits in women, where restenosis rates from smaller vessel size and higher concomitant diabetes mellitus are problematic. Thus, Movahed et al add value to our understanding of women with CAD by highlighting again the need to be cognizant of the poorer outcomes that certain women with CAD face. However, the available literature shows a benefit of PCI in women at high risk for ischemic complications and should not be withheld in these patients. To the contrary, Movahed’s findings suggest that PCI has not alone eliminated the disparities in outcomes and that there is a pressing need to develop further therapies and adjuncts to PCI to help fully eliminate the “gender gap.”

References

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_______________________________________ From Cardiology Consultants, Christiana Hospital, Neward, Delaware. The author reports no conflicts of interest regarding the content herein. Address for correspondence: Ruchira Glaser, MD, MSCE, FACC, Cardiology Consultants, PA, 252 Chapman Road, Newark, DE 19702. E-mail: ruglaser@gmail.com