Author + information
- Received April 26, 1996
- Revision received September 4, 1996
- Accepted September 20, 1996
- Published online January 1, 1997.
- James H O’Keefe Jr., MD, FACCA,*,
- Susie C Kim, MDA,
- Ralph R Hall, MDA,
- Vicki C CochranA,
- Stephanie L Lawhorn, MD, FACCA and
- Ben D McCallister, MD, FACCA
- ↵*Dr. James H. O’Keefe, Jr., Cardiovascular Consultants, Inc., 4330 Wornall Road, Suite 2000, Kansas City, Missouri 64111.
Objectives. The purpose of this study was to assess the effects of estrogen replacement therapy on long-term outcome, including restenosis, myocardial infarction, stroke and death after a first percutaneous transluminal coronary angioplasty (PTCA) procedure, in postmenopausal women.
Background. Observational and epidemiologic studies, basic laboratory research and clinical trials consistently suggest that estrogen replacement therapy is associated with beneficial cardiovascular effects in women. These cardioprotective actions may be particularly relevant to women with coronary artery disease, such as those who have undergone PTCA.
Methods. This was a retrospective study that included 337 women who underwent elective PTCA between 1982 and 1994. The treatment group consisted of 137 consecutive women receiving long-term estrogen therapy at the time of elective PTCA and during follow-up. The control group comprised 200 women who were computer-matched with the estrogen group. The mean follow-up period was 65 ± 35 months.
Results. Actuarial survival was superior in the estrogen group; the 7-year survival rate was 93% for the estrogen group versus 75% for the control group (p = 0.001). The cardiovascular event rate (death, nonfatal myocardial infarction or nonfatal stroke) was significantly lower in the estrogen group at 7 years (12% vs. 35% in the control group, p = 0.001). The need for subsequent revascularization during follow-up was similar in the two groups. Multivariable analysis identified diabetes, estrogen therapy (adjusted risk ratio 0.38, 95% confidence interval 0.19 to 0.79) and left ventricular ejection fraction <40% as independent correlates of cardiovascular death or myocardial infarction during follow-up.
Conclusions. Estrogen replacement therapy was associated with an improved long-term outcome after PTCA in postmenopausal women.
(J Am Coll Cardiol 1997;29:1–5)>
Coronary artery disease, while rare in premenopausal women, becomes more prevalent after menopause, resulting in a lifetime risk of coronary artery disease (∼1 of every 2 women) that is similar to that of men ([1, 2]). Consistent and extensive data from observational studies ([1, 3]) have shown that estrogen replacement therapy is associated with a significant reduction in the risk of coronary artery disease for a general population of postmenopausal women considered to be at average risk for heart disease. Despite an increased risk of endometrial cancer (which can be eliminated by the addition of progestin to the hormone replacement regimen []) and a marginally significant increased risk of breast cancer (), estrogen therapy has been associated with significant reductions in all cause mortality (). The benefits of estrogen replacement therapy have been considered impressive enough to prompt recommendations from the American College of Physicians task force () suggesting that “all women should consider taking preventive hormone therapy.”
Adverse cardiac events including death and myocardial infarction are at least as common in women as in men during short- and long-term follow-up after elective percutaneous transluminal coronary angioplasty (PTCA) ([6, 7]). Secondary prevention (the use of preventive therapy in the setting of established disease) generally is more clinically effective and cost-effective than primary prevention (). The observational secondary prevention studies published to date ([9–12]) have shown estrogen to be associated with a 70% to 90% lower risk of death in women with established coronary artery disease.
Estrogen has multiple potentially beneficial effects on the cardiovascular system including decreased low density lipoprotein, lipoprotein(a), and fibrinogen levels; increased high density lipoprotein and apolipoprotein A-1 levels; and improved endothelial function, vascular compliance, fibrinolytic potential and antioxidant activity ([13–19]). Although some of these estrogen effects might be expected to reduce the risk of restenosis after PTCA, all of these effects should improve long-term cardiovascular risk in women with established coronary artery disease. This study was designed to evaluate the long-term outcomes after elective PTCA in women as a function of their hormone replacement status.
This retrospective study was performed on a comprehensive prospectively collected data base that includes all patients who have undergone PTCA at the Mid America Heart Institute since 1981. This data base is updated systematically to ensure complete and accurate follow-up. A total of 2,436 women underwent elective PTCA between 1982 and 1994 and were considered for possible inclusion in the study. Patients who underwent PTCA in the setting of acute or recent myocardial infarction or who had previously undergone PTCA were excluded. The information regarding hormone replacement therapy was not prospectively entered into the data base; rather, it was verified initially through chart review and later confirmed with patient or family interviews, or both, and a mailed questionnaire. Hormone replacement status was available for all patients; if this information was unavailable or uncertain, the woman was excluded from the study. One-hundred-thirty-seven postmenopausal women were identified consecutively who were receiving long-term estrogen replacement therapy both at the time of elective PTCA and during the follow-up period. All of the women in the estrogen group had been taking estrogen for 1 month before PTCA. Continued hormone use during the study was assessed by written questionnaire and interviews. A total of 16 women in the estrogen group (11.7%) discontinued hormone therapy during follow-up for reasons including side effects in 3, noncompliance in 4, advice from their physician that hormone replacement was unnecessary in 6, the occurrence of breast cancer in 2 women and development of breast cancer in a sister of 1 woman. However, 13 of these 16 women received estrogen during the majority of the follow-up period. This group of 137 women receiving hormone replacement therapy was then computer-matched for age, left ventricular ejection fraction, number of diseased vessels and completeness of revascularization with 200 postmenopausal women who were not receiving hormone replacement therapy either at the time of PTCA or at any time during follow-up. Follow-up complete through 1995 averaged 65 ± 35 months. For patients who died during the study, the cause of death was determined by the use of chart review, family phone interviews, death certificates and autopsy reports when available.
1.1 Statistical analysis.
The major end points of the study included all cause death, cardiac death, nonfatal myocardial infarction, nonfatal stroke and restenosis requiring repeat revascularization. Actuarial survival rates were calculated with Kaplan-Meier analysis and were analyzed by using log-rank comparison. Event-free survival was predefined as freedom from death, nonfatal myocardial infarction and nonfatal stroke during follow-up. A multivariable analysis using the Cox proportional hazards model was performed by assessing factors correlated with myocardial infarction or cardiac death during follow-up after PTCA. Categoric variables were compared by using chi-square and Fisher exact tests. Continuous variables were assessed by Student ttest.
A total of 337 postmenopausal women were included in this study. Baseline variables of the two groups are outlined in Table 1. The groups were not significantly different with respect to nearly all baseline angiographic and clinical variables. The proportion of patients with diabetes was significantly higher in the control group (28%) than in the estrogen group (18%, p = 0.043). Seventy-two percent of the women in the estrogen group had previously undergone hysterectomy compared with 47% in the control group (p < 0.001). In the estrogen group, oral conjugated estrogens were utilized in 72% (mean dose 0.72 mg/day), oral estradiol in 11% (mean dose 1.12 mg/day), transdermal estrogen in 4% and concomitant oral estrogen and progestin in 13% of the women.
In-hospital complications (myocardial infarction, need for urgent coronary bypass surgery, or death) occurred in 7 (5.1%) of 137 women in the estrogen group and in 11 (5.5%) of 200 women in the control group (p = NS). During the course of the study, there were 11 deaths (8%) in the estrogen group and 45 (22.5%) in the control group (p = 0.0003). During follow-up, cardiac death of myocardial infarction occurred in 11 (8%) of 137 women in the estrogen group and in 41 (20.5%) of 200 in the control group (p = 0.002). Adverse cardiovascular events including death, myocardial infarction or stroke occurred in 18 patients (13%) in the estrogen group and in 63 (31%) in the control group (p = 0.0001). Table 2outlines the incidence of adverse cardiovascular events in the two groups. Kaplan-Meier analyses of overall survival and event-free survival (Fig. 1) demonstrated a better outcome in the estrogen group than in the control group. By actuarial analysis, the estrogen group experienced a 69% reduction in risk of death, myocardial infarction or stroke over the 7-year follow-up period. Actuarial 7-year survival rate was 93% for the estrogen group versus 75% for the control group (p = 0.001). The incidence of subsequent revascularization procedures was similar in the two groups (Fig. 2).
The causes of death during the study are outlined in Table 3. The death was of cardiovascular origin in approximately two thirds of the patients who died during the study.
The multivariable analysis identified previous diabetes (risk ratio 2.9), estrogen therapy (risk ratio 0.38) and left ventricular ejection fraction <40% (risk ratio 3.9) as independent correlates of myocardial infarction or cardiac death after PTCA (Table 4).
This study suggests that estrogen replacement therapy is associated with improved long-term outcome after elective PTCA in postmenopausal women. Although estrogen replacement therapy was associated with a decreased risk of all cause mortality and cardiovascular events, the need for repeat PTCA during long-term follow-up was not different in the estrogen-treated women. The incidence of fatal or nonfatal cancer over a 7-year period was similar in the two groups, although the size of this study was inadequate to draw any conclusions about this end point. On multivariable analysis, the lack of estrogen replacement therapy along with diabetes and ejection fraction <40% were correlated with cardiac death or myocardial infarction during long-term follow-up after PTCA.
Estrogen use in postmenopausal women without heart disease has been shown ([1, 3, 20]) to provide powerful protection against coronary artery disease. Extensive observational data suggest that the risk ratio of cardiovascular events associated with estrogen replacement therapy in the setting of primary prevention is between 0.37 and 0.79. The risk ratio for cardiovascular events in the current study involving women with established coronary artery disease was 0.38. In women with clinically evident coronary artery disease, the eventual cause of death is most likely to have a cardiovascular etiology ([6, 19]). Death was of cardiovascular origin in approximately two thirds of the patients who died. Thus, for postmenopausal women who have undergone PTCA, the potential benefits of estrogen therapy are magnified by their increased risk of cardiovascular morbidity and mortality.
Estrogen has been shown () to improve endothelial function in diseased atherosclerotic vessels in women but not in men. This improvement is manifested as a reversal of inappropriate acetylcholine-mediated vasoconstriction in atherosclerotic coronary artery segments. Other studies () have suggested that an increase in the fibrinolytic potential may be a significant factor in the cardioprotective effects of estrogen. Postmenopausal women receiving estrogen replacement therapy have lower plasminogen activator inhibitor antigen levels and fibrinogen levels than do postmenopausal women not receiving estrogen. Additionally, tissue plasminogen activator antigen levels () are higher in women receiving estrogen replacement therapy than in those not receiving hormone therapy. Many of these factors are intimately involved in acute ischemic cardiovascular syndromes.
These data suggest that estrogen replacement therapy may be effective in reducing cardiovascular events even when it is started after the clinical appearance of coronary artery disease. Parallels can be made between estrogen replacement therapy and lipid-lowering therapies with respect to the reduction of acute cardiovascular events. Effective lipid-lowering therapy has been shown () to result in minimal (probably clinically unimportant) lesion regression but remarkable reduction in up to 50% to 70% of coronary events. This reduction appears to be mediated through a reduction in the incidence of inflamed ulcerated/thrombotic plaques that are associated with most acute cardiovascular events (). Estrogen replacement therapy may, in a similar fashion, stabilize atherosclerotic lesions, leading to a lower rate of adverse cardiovascular events without significantly reducing the overall atherosclerotic burden.
Estrogen replacement therapy was shown in one study () to decrease the risk of restenosis after coronary atherectomy but not after PTCA. The mechanism of benefit of estrogen replacement therapy after PTCA in the current study was not conferred through a reduction in the risk of restenosis; the need for subsequent revascularization procedures was similar in the two groups. Combination estrogen/progestin hormone replacement therapy was used by 13% of the women in the estrogen group. Progestin therapy has been shown () to offset some of the lipid benefits of unopposed estrogen. The small number of women receiving combination therapy in the current study precluded the meaningful subgroup analysis needed to address this issue. A recently published large observational study of 59,000 women () concluded that the addition of progestin did not attenuate the cardioprotective effects of postmenopausal estrogen therapy. That study () showed the adjusted relative risk for cardiac death or myocardial infarction to be 0.39 in the estrogen/progestin users and 0.60 in the estrogen alone group compared with that of postmenopausal women not receiving hormone therapy.
3.1 Study limitations.
This is a retrospective study that involved relatively small numbers of patients. Although the groups were matched for most important clinical variables, it is possible that a selection bias was present whereby women who were receiving estrogen replacement therapy were an intrinsically healthier cohort. A trend toward a higher rate of subsequent angioplasty was noted in the estrogen group, and diabetes was more common in the control group. These differences and other unmeasured confounding variables might account in part for the apparent differences in outcome in the women receiving estrogen. These data demonstrate an association between estrogen and a decreased risk of cardiovascular events but do not prove causality. Double-blind randomized clinical trials are currently in progress studying the effects of hormone replacement therapy in postmenopausal women. Definitive conclusions about the benefits of estrogen in women with coronary artery disease need to be deferred until these data are available. In the meanwhile, the results of the current study in conjunction with extensive published data suggest that hormone replacement therapy is a logical but still unproved intervention for women with established coronary artery disease. The decision to initiate estrogen replacement therapy should be individualized for each woman. The risks and benefits of estrogen will need to be discussed with the patient in the context of her specific situation and family history. If hormone replacement therapy is initiated, a plan for periodic gynecologic and breast examinations should be outlined.
In summary, estrogen replacement therapy for postmenopausal women was associated with a significantly better long-term survival after elective PTCA.
We acknowledge Lori Maher for expertise in manuscript preparation.
This work was presented in part at the 68th Annual Scientific Sessions of the American Heart Association, Anaheim, California, November 1995.
- Received April 26, 1996.
- Revision received September 4, 1996.
- Accepted September 20, 1996.
- The American College of Cardiology
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