Differences in Prognostic Factors and Outcomes Between Women and Men Undergoing Coronary Artery Stenting FREE

Despite major advances in the diagnosis and treatment of heart disease, coronary artery disease (CAD) remains the leading cause of morbidity and mortality in both men and women in developed countries. At any given age, the prevalence of CAD is greater in men than in women.^1- 2 Nonetheless, several recent reports have concluded that women with CAD have a worse prognosis than men with this disease.^3- 10 A number of likely explanations for this difference in outcome have been described.^11- 12 Besides differences in baseline characteristics between women and men, sex-bias in the use of cardiac procedures frequently,^6,13- 16 but not consistently,^17- 18 has been reported. The underuse of cardiac procedures among women has been related to the "Yentl syndrome"¹¹ but the less favorable outcome of female patients treated with either coronary artery bypass graft (CABG) surgery^19- 21 or percutaneous transluminal coronary angioplasty (PTCA)^22- 24 may also serve as an explanation.

Coronary artery stenting has become the mainstay of catheter-based interventions for patients with CAD.²⁵ Stenting has improved the outcome of various subsets of patients compared with conventional PTCA^26- 30 and attenuated the negative prognostic role of known risk factors such as diabetes.³¹ The large and increasing experience with coronary stenting may enable an assessment of sex-related differences in the risk profile and outcome and of the potential benefit that women may obtain from this treatment strategy. Thus, it was the purpose of this study to examine whether there are sex-based differences in prognostic factors as well as early and late outcome in patients undergoing coronary stent placement.

From May 1992 through December 1998, 6532 patients (23.7% women, 76.3% men) with symptomatic CAD underwent a percutaneous coronary intervention at the Deutsches Herzzentrum and 1. Medizinische Klinik der Technischen Universität, Munich, Germany. Of these, 1218 patients (25.0% women, 75.0% men) underwent conventional PTCA alone and were not eligible for this analysis, which focused on coronary stenting. An additional 1050 patients (23.1% women, 76.9% men) who underwent stenting in the setting of acute myocardial infarction (MI) were excluded from this study. Thus, the study population consisted of 4264 consecutive patients, 1001 women (23.5%) and 3263 men (76.5%), with stable or unstable angina pectoris treated with coronary artery stenting (Table 1). All patients gave written informed consent before the intervention.

The stent placement technique and periprocedural antithrombotic regimen have been described previously.^32- 33 All patients were given 100 mg of aspirin orally, twice daily, indefinitely. In the initial phase of our study, patients were treated with anticoagulant agents (heparin sodium for 5-10 days, phenprocoumon for 4 weeks). Later, the standard regimen consisted of 250 mg of ticlopidine hydrochloride twice daily for 4 weeks. During the last 3 and a half years of the study period, patients considered at higher risk for stent thrombosis (eg, large residual dissections, thrombus at the stent site) received abciximab.

Procedural results were assessed by angiography. The procedure was considered successful when stent placement was associated with a residual stenosis of less than 30% and Thrombolysis in Myocardial Infarction (TIMI) flow grade of 2 or more.³⁴

The definition of complex lesions used was described previously.^35- 36 Briefly, a number of lesion characteristics such as location, length, tortuosity, angulation, calcification, presence of thrombus, and total occlusions were used to classify the lesions according to a 4-scale score, A, B1, B2, and C; lesions of type B2 or C were considered complex. Left ventricular function was assessed qualitatively on the basis of biplane angiograms using a 7-segment division; the diagnosis of reduced left ventricular function required the presence of hypokinesia in at least 2 segments. In 3017 patients (71%), 2310 men and 707 women, quantitative assessment of left ventricular ejection fraction was performed. Digital angiograms were analyzed offline with the automated edge detection system CMS (Medis Medical Imaging Systems, Nuenen, Netherlands). The parameters obtained were minimal lumen diameter, reference diameter, diameter stenosis, and diameter of the maximally inflated balloon during stent placement.

The diagnosis of unstable angina at presentation was based on a history of crescendo angina, angina at rest or with minimal exertion, or angina of new onset (within 1 month) in the absence of clear-cut electrocardiographic and cardiac enzyme changes diagnostic of an acute MI.³⁷ Death from any cause, MI, and target vessel revascularization (PTCA or CABG surgery) were considered as adverse events.

The diagnosis of acute MI was established in the presence of at least 2 of the following criteria: clinical episode of prolonged chest pain, the appearance of 1 or more new pathologic Q waves on the electrocardiogram, and the increase in creatine kinase (or its MB isoenzyme) levels to at least twice the upper normal limit. Target vessel revascularization was performed in the presence of angiographic restenosis and symptoms or signs of ischemia.

The main end point of this analysis was the combined event rate of death and MI. The follow-up protocol included a telephone interview at 30 days, a clinical visit at 6 months, and an additional telephone interview at 1 year after the procedure. For patients reporting cardiac symptoms during the telephone interview, at least 1 clinical and electrocardiographic follow-up visit was scheduled and performed at the outpatient clinic or by the referring physician. At 1 year, all information derived from eventual hospital readmission records or provided by the referring physician or by the outpatient clinic was entered into the computer database.

The results are expressed as mean (SD) or as proportions (percentages). The differences between groups were assessed using χ² test or Fisher exact test for categorical data and t test for continuous data. Survival analysis was performed applying the Kaplan-Meier method. Differences in survival parameters were assessed for significance by means of the log-rank test.

The unadjusted and adjusted risk associated with female sex was assessed using the hazard ratios (HRs) and 95% confidence intervals (CIs) derived from univariate and multivariate Cox regression models, respectively. A patient's sex together with clinical and angiographic factors that were significantly different between women and men in univariate analysis were entered into the multivariate Cox model to adjust for baseline differences. All variables were entered into the model in their original form without transformation. We also tested whether there was an interaction between sex and age by entering into this model the interaction term gender age. The HRs for continuous variables reflect the hazard for patients at the 75th percentile of the distribution of the variable compared with patients at the 25th percentile.

Stratification according to different risk subsets was made by classification and regression tree (CART) analysis.³⁸ A disadvantage of this method is that it does not take into account the possible interplay of the risk factors entered into the model. For this reason, the CART model included only the independent correlates of the outcome as determined by the multivariate Cox model described above. All analyses were performed using the S-Plus statistical package (Mathsoft Inc, Seattle, Wash). Statistical significance was accepted for all values of P<.05.

Compared with men, women were more likely to have hypertension, diabetes, and hypercholesterolemia but were less likely to be smokers (Table 1). Conversely, a relatively smaller proportion of women than men had multivessel disease, reduced left ventricular function, and a history of MI or CABG surgery. In women compared with men, the lesions involved more often the left anterior descending coronary artery and were situated in vessels of smaller size (Table 2). The procedural data were essentially similar with regard to balloon-to-vessel ratio, stent model implanted, total stented length, and final diameter stenosis. Procedural success was achieved in 98.2% of both women and men. There were no differences in relationship to antithrombotic therapy used during and after the procedure. The use of concomitant pharmacologic therapy was also comparable with a high proportion of patients taking angiotensin-converting enzyme inhibitors, β-blockers, and statins.

Compared with men, women had a significantly higher risk of death or nonfatal MI during the first 30 days after coronary artery stent placement (Table 3), unadjusted HR of 1.70 (95% CI, 1.10-2.62). In multivariate analysis, female sex was a significant independent risk factor for adverse events, adjusted HRs of 2.02 (95% CI, 1.27-3.19). The HRs for other independent risk factors were reduced left ventricular function, 1.77 (95% CI, 1.13-2.75); older age, 1.67 (95% CI, 1.09-2.56), for an age of 73 years (75th percentile) vs 57 years (25th percentile); and diabetes, 1.58 (95% CI, 1.00-2.56). Coronary vessel size did not correlate with the 30-day outcome as reflected by an HR of 1.00 (95% CI, 0.75-1.33) for a vessel size of 2.6 mm (25th percentile) vs 3.3 mm (75th percentile). However, there was a significant interaction (P = .01) between sex and age as a result of a stronger association with age for the 30-day outcome in men.

The excess risk of the composite end point of death or nonfatal MI among women generally declined during the first months after the intervention (Figure 1). At the end of the 1-year period, however, both women and men had a comparable cumulative incidence of this end point with 6.0% in women and 5.8% in men (P = .77). The unadjusted HR associated with female sex was 1.04 (95% CI, 0.78-1.40).

In a multivariate model similar to that for the 30-day period, the adjusted HR for the end point of death or MI at 1 year was 1.06 (95% CI, 0.75-1.48) for women. The HRs for independent risk factors identified by this analysis were: age, HR of 2.07 (95% CI, 1.63-2.64) for an age of 73 years (75th percentile) vs 57 years (25th percentile); reduced left ventricular function, 1.73 (95% CI, 1.33-2.26); diabetes, 1.50 (95% CI, 1.14-1.98); and smoking habit, 1.42 (95% CI, 1.05-1.91). There was no significant interaction (P = .18) between sex and age in this model.

To assess whether the risk stratification according to these factors was similar in women and men, we applied a CART analysis and identified subsets with a different 1-year risk for death or nonfatal MI both in women and men (Figure 2). Among female patients, the risk extremes yielded by this analysis were between 3.4% for nondiabetic women younger than 70 years and 16.7% for diabetic women 70 years or older who had reduced left ventricular function (Figure 2). Among male patients, the risk extremes were between 3.3% for patients younger than 70 years with normal left ventricular function and 13.7% for older patients with reduced left ventricular function. The following difference in the relevance of risk factors between women and men was observed: while diabetes followed by older age were the most important factors in female patients, the outcome of male patients was mostly influenced by an older age followed by a reduced left ventricular function.

The cumulative 1-year mortality was 4.0% in women and 4.1% in men (P = .94). Regarding the risk of death at 1 year, female sex was associated with an unadjusted HR of 0.99 (95% CI, 0.69-1.40) and an adjusted HR of 0.78 (95% CI, 0.54-1.13). A distinctive risk pattern for women and men similar to that shown above by the CART analysis was also evident for mortality. The major risk factor for death at 1 year was diabetes in women and older age in men. The risk increase that accompanied the presence of diabetes was 3.37 (95% CI, 1.80-6.33) in women and 1.59 (95% CI, 1.09-2.31) in men. The risk increase that accompanied the presence of older age (≥70 years) was 3.34 (95% CI, 2.36-4.71) in men and 2.61 (95% CI, 1.27-5.35) in women.

Subsequent revascularization procedures (either CABG surgery or PTCA) due to clinical and angiographic occurrence of restenosis were less frequently needed in women (14.5% vs 17.5% in men; P = .02). Among these reinterventions, the rate of CABG surgery was essentially the same (1.9% in women, 2.2% in men; P = .52).

The main finding of this study indicates that women are expected to have the same 1-year outcome as men after coronary artery stenting. Other findings of the study are that compared with men, women undergoing coronary stent placement present substantial differences in baseline characteristics, in the temporal pattern of outcome, and in the relative value of the prognostic factors, all of which may have relevant implications in clinical practice.

We analyzed a consecutive series of patients with stable or unstable angina who underwent intracoronary stenting. The unselected nature of the population encompassed in this study is representative of the current practice of percutaneous coronary interventions and comparable with that of the series enrolled in the most recent randomized trials of coronary stenting.³⁹

There were pronounced differences in baseline characteristics between women and men. Except for having a lower prevalence of smoking, women presented with a higher prevalence of cardiovascular risk factors. Women generally develop CAD between 6 and 10 years later than men² as a result of the protective role of endogenous estrogen.⁴⁰ This explains the older age of female patients in our cohort and, as a consequence, the denser aggregation of risk factors among women. Yet, women had less severe CAD, considering the proportion of patients with multivessel disease, and they were less likely to have prior MI and reduced left ventricular function. The reason for this apparent dissociation between prevalence of risk factors and severity of ischemic heart disease, which has also been described previously,⁴¹ is not completely clear. In cohort studies of patients with percutaneous coronary interventions, this may reflect a sex bias with women more likely to be denied access to these procedures in the presence of more advanced CAD. Differences between men and women in the initial presentation of CAD may be an alternative explanation. Framingham data have shown that women with CAD are more likely to present with angina pectoris initially whereas men first present with MI.⁴² This may increase the chances of women to be percutaneously treated when left ventricular function is still preserved.

During the early phase (30 days) after coronary stenting, women in our study experienced more adverse events than did men. In particular, the risk of death or MI was significantly higher among women even after adjustment for baseline differences. Stent thrombosis accounts for most of the early complications after stenting.⁴³ Thus, women appear to be at higher risk for thrombotic complications. This finding is consistent with previous studies after PTCA, which have almost invariably shown the increased early hazard carried by women.^{22- 24,44- 45} As with the findings of our study, other studies have also shown that the differences in conventional baseline characteristics may not sufficiently explain this risk increase. In a large series of patients undergoing PTCA, Malenka et al²⁴ found that the risk of in-hospital death remained elevated in women even after adjusting for case-mix. A sex-specific influence of genetic factors cannot be excluded. As an example, we reported previously that a genetic variant of platelet glycoprotein IIIa increases the risk of restenosis after stenting more in women than in men.⁴⁶

Our data also show that the excess risk observed in women gradually diminishes and, at the end of the 1-year follow-up period, both men and women have essentially identical outcomes. In addition, women required less reinterventions after 30 days. A similar outcome pattern was also shown in the early PTCA Registry of the National Heart, Lung, and Blood Institute.⁴⁴ In that registry, although in-hospital mortality was significantly higher in women compared with men, the cumulative mortality at 18 months was virtually the same⁴⁴ and rate of reintervention was lower among women.However, the study reported on patients with a particularly low-risk profile who were treated in the early phase of PTCA, and therefore the findings may not be comparable with current practice. Subsequent reports have generally shown that the initial difference in mortality to the disadvantage of women is maintained for years after PTCA.^22- 23,45 Our 1-year findings are consistent with the results of a more recent study that showed no sex-specific differences in outcome among patients treated with either PTCA or CABG.⁴⁷ Thus, greater experience and advances in interventional cardiology and surgery may have improved the results of coronary interventions, especially in female patients,^48- 49 and reduced the excess risk previously described for women.

Age, diabetes, left ventricular function, and smoking were the independent correlates of 1-year outcome in the entire population analyzed in our study, but their prognostic strength presented a sex-based difference. Multivariate risk stratification methods such as CART analysis applied to men and women, separately, showed that older age was the major determinant of an adverse outcome in men whereas diabetes had the greatest prognostic value in women. The weaker age dependence of outcome in women treated with coronary artery stenting may be relevant to the issue of the definition of treatment guidelines, considering the older age with which women present with symptomatic CAD. To our knowledge, however, differences in the prognostic pattern after percutaneous coronary interventions have not been described previously and further studies are needed before trying to draw definitive implications.

Our findings of a comparable 1-year outcome among women and men following coronary artery stenting do not justify a less aggressive treatment approach of CAD in women than in men, as observed in several previous studies.^6,13- 16 The greater hazard presented by women was only confined to the early poststenting period. With the availability of new, effective antithrombotic drugs such as the glycoprotein IIb/IIIa inhibitors, there is a potential to reduce the early excess risk and improve the overall results of coronary interventions in women. This hope is further strengthened by considering the specific nature of prognostic factors in women. The postinterventional outcome in women depended primarily on potentially modifiable factors such as diabetes. Women with diabetes undergoing coronary stenting can especially benefit from a better control of glycemia. In addition, recent findings suggesting a more pronounced salutary effect of glycoprotein IIb/IIIa inhibition among patients with diabetes, who were treated with coronary stenting,⁵⁰ may open encouraging prospects for women with diabetes who undergo this procedure.

The main limitation of this study is that it offers data only about coronary stenting in women. The inclusion of other revascularization techniques, such as CABG surgery and PTCA, is indispensable for the establishment of the optimal treatment strategy for women with CAD.

Moreover, the patients included in this study were referred for diagnostic coronary angiography by family physicians. This may be the source of another limitation of this study due to the possible referral bias that generally affects studies performed in tertiary medical centers. Referring physicians may use different, sex-specific, symptomatic, and functional thresholds for referring patients for invasive diagnostic tests. In our study, we are unable to evaluate the magnitude of this potential bias which has been the focus of extensive work in the past.^6,13- 18

In conclusion, the results of this study indicate that the 1-year outcome for women with CAD undergoing coronary artery stenting is similar to that for male patients. Despite the similarity in outcome, there are several sex-specific differences in baseline characteristics and clinical course after the intervention. In addition, differences in the relative weight of prognostic factors may aid in clinical decision making and help to further reduce the risk and improve the outcomes of coronary interventions in women.