Mehilli J, Kastrati A, Dirschinger J, Bollwein H, Neumann F, Schömig A. Differences in Prognostic Factors and Outcomes Between Women and Men Undergoing Coronary Artery Stenting. JAMA. 2000;284(14):1799-1805. doi:10.1001/jama.284.14.1799
Author Affiliations: Deutsches Herzzentrum (Drs Mehilli, Kastrati, Dirschinger, Bollwein, and Schömig) and 1. Medizinische Klinik rechts der Isar (Drs Neumann and Schömig), Technische Universität, Munich, Germany.
Context Women with coronary artery disease (CAD) are believed to have a higher
risk for adverse outcomes than men after conventional coronary interventions.
The increasing use of coronary stenting has improved the outcome of patients
undergoing coronary interventions, but little is known about the nature of
outcomes in men vs women after this procedure.
Objective To examine whether there are sex-based differences in prognostic factors
and in early and late outcomes among CAD patients undergoing coronary stent
Design, Setting, and Patients Inception cohort study, at 2 tertiary referral institutions in Germany.
Consecutive series of 1001 women and 3263 men with symptomatic CAD who were
treated with stenting between May 1992 and December 1998. Patients who underwent
stenting in the setting of acute myocardial infarction were excluded.
Main Outcome Measure The combined event rates of death and nonfatal myocardial infarction,
assessed at 30 days and 1 year after stenting and compared by sex.
Results Compared with men, women undergoing coronary stenting were significantly
older (mean age, 69 vs 63 years) and more likely to present with diabetes,
arterial hypertension, or hypercholesterolemia. Women had less extensive CAD,
a less frequent history of myocardial infarction and better preserved left
ventricular function than men. Women presented an excess risk of death or
nonfatal myocardial infarction only during the early period after stenting:
the 30-day combined event rate of death or myocardial infarction was 3.1%
in women and 1.8% in men (P = .02) and the multivariate-adjusted
hazard ratio (HR) for women was 2.02 (95% confidence interval [CI], 1.27-3.19).
At 1 year, the outcome was similar for both women and men (combined event
rate for women, 6.0%, and for men, 5.8% (P = .77);
multivariate-adjusted HR for women, 1.06 [95% CI, 0.75-1.48]). There was a
sex difference in the prognostic value of baseline characteristics: the strongest
prognostic factors were diabetes in women and age in men.
Conclusions The results of this study indicate that 1-year outcomes of women with
CAD undergoing coronary artery stenting are similar to those of men. Despite
the similarity in outcomes, there are several sex-specific differences in
baseline characteristics, clinical course after the intervention, and relative
weight of prognostic factors.
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) surgery19- 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 PTCA26- 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,
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
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.