Cardiovascular Effects of Tamoxifen in Women With and Without Heart Disease: Breast Cancer Prevention Trial

Steven E. Reis, Joseph P. Costantino, D. Lawrence Wickerham, Elizabeth Tan-Chiu, Jiping Wang, Maureen Kavanah, For the National Surgical Adjuvant Breast Bowel Project Breast Cancer Prevention Trial Investigators

Affiliations of authors: S. E. Reis, Cardiovascular Institute, University of Pittsburgh Medical Center, PA; J. P. Costantino, J. Wang, University of Pittsburgh Graduate School of Public Health; D. L. Wickerham, E. Tan-Chiu, National Surgical Adjuvant Breast and Bowel Project and Allegheny General Hospital, Pittsburgh; M. Kavanah, Boston Medical Center, MA.

Correspondence to: Steven E. Reis, M.D., University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213 (e-mail: reisse{at}msx.upmc.edu).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: The overall effect of prophylactic tamoxifen in women depends on the balance between the effects of the drug, which include preventing breast cancer and altering cardiovascular risk. In a recent clinical trial, postmenopausal estrogen–progestin therapy was shown to increase the risk of early cardiovascular events among women with a history of coronary heart disease (CHD). The cardiovascular effects of tamoxifen in women with and without CHD are not known. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) is the only clinical trial that provides data to assess the cardiovascular effects of tamoxifen in women with and without CHD. Methods: A total of 13 388 women at increased risk for breast cancer were randomly assigned in the BCPT to receive either tamoxifen (20 mg/day) or placebo. Cardiovascular follow-up was available for 13 194 women, 1048 of whom had prior clinical CHD. Fatal and nonfatal myocardial infarction, unstable angina, and severe angina were tabulated (mean follow-up: 49 months). All statistical tests were two-sided. Results: Cardiovascular event rates were not statistically significantly different between women assigned to receive tamoxifen and those assigned to receive placebo, independent of pre-existing CHD. Among women without CHD (6074 on tamoxifen versus 6072 on placebo), risk ratios (95% confidence intervals [CIs]) for tamoxifen users were 1.75 (0.44 to 8.13) for fatal myocardial infarction, 1.11 (0.55 to 2.28) for nonfatal myocardial infarction, 0.69 (0.29 to 1.57) for unstable angina, and 0.83 (0.32 to 2.10) for severe angina. In women with CHD (516 on tamoxifen versus 532 on placebo), risk ratios (95% CIs) for tamoxifen users were 0.00 (0 to 1.58) for fatal myocardial infarction, 1.25 (0.32 to 5.18) for nonfatal myocardial infarction, 2.26 (0.87 to 6.55) for unstable angina, and 1.39 (0.23 to 9.47) for severe angina. There was no evidence that the lack of association between tamoxifen and cardiovascular events was related to an early increase in risk that may have been offset by a late decrease in risk. Conclusion: When used for breast cancer prevention in women with or without heart disease, tamoxifen is not associated with beneficial or adverse cardiovascular effects.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Tamoxifen is a nonsteroidal compound with mixed estrogen agonist and antagonist properties and is effective in breast cancer prevention in women (1). Consideration of the risk/benefit ratio of tamoxifen is necessary before recommendation of its widespread use for preventive therapy. As is the case for estrogen, tamoxifen's anti-atherosclerotic properties suggest that its use is expected to decrease cardiovascular risk (25). However, a randomized clinical trial (6) has demonstrated that the anticipated beneficial clinical cardiovascular effects of estrogen–progestin therapy in postmenopausal women with pre-existing heart disease is not evident. In fact, the data demonstrate an early harmful effect of traditional hormone therapy for this subgroup of women at high risk for cardiovascular events. Since the observed effect of these hormones was opposite to that which was anticipated, it is important to determine if the same may be true for tamoxifen. Because cardiovascular disease is the leading cause of mortality in women in the United States, accounting for nearly 500 000 deaths each year (7), a potential increase in cardiovascular risk could appreciably offset the beneficial effects of tamoxifen on breast cancer prevention in women.

The double-blind, randomized, placebo-controlled National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) (1) reported previously that tamoxifen did not influence cardiovascular risk in 13 388 women. The goal of the present study is to identify the cardiovascular effects of tamoxifen in groups of women at high and low risk for cardiovascular events. Accordingly, the cardiovascular effects of tamoxifen were evaluated in 1048 women with and 12 146 without pre-existing clinical coronary heart disease (CHD) who were enrolled in the NSABP BCPT.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Specific methods of the NSABP BCPT have been reported separately (8). Eligibility criteria included 1) women of ages 60 years or more, of ages 35–59 years and with a 5-year predicted breast cancer risk of at least 1.66% (9), or a history of lobular breast carcinoma in situ, 2) life expectancy of 10 years or more, 3) breast examination and mammogram without evidence of cancer, 4) no hormonal therapy within 3 months prior to randomization, and 5) no history of deep venous thrombosis or pulmonary embolism. After providing written informed consent approved by their local institutional review board, the subjects were randomly assigned to receive tamoxifen (20 mg/day) or placebo and were followed for measures of breast, cardiovascular, and osteoporosis outcomes. This study represents updated follow-up as compared with the original NSABP report with complete cardiovascular event information through the date of unblinding (1). The median follow-up of the study cohort included for this article is 57 months; the mean follow-up is 49 months. During this period of long-term follow-up, 76% of the tamoxifen participants were compliant with the study therapy; 83% were compliant through 24 months of follow-up. To evaluate the effects of tamoxifen in women with and without pre-existing heart disease, we divided the 13 388 women enrolled at one of 131 clinical sites into subgroups of those with and without a self-reported history of clinical CHD, defined as myocardial infarction or angina prior to randomization.

Cardiovascular outcomes.

Medical records for subjects with suspected cardiovascular events were collected by the clinical sites and forwarded to the NSABP Operations Center for adjudication by investigators who were blinded to treatment assignment (S. E. Reis, E. Tan-Chiu, and D. L. Wickerham). Primary cardiovascular events included fatal myocardial infarction, Q-wave myocardial infarction (required at least two of the following: new, significant [i.e., >=0.04 seconds] Q-wave on electrocardiogram [EKG], characteristic chest pain, and noteworthy cardiac enzyme elevation), and non-Q-wave myocardial infarction (cardiac enzyme elevation without new Q-waves on EKG). Secondary cardiovascular events included unstable angina (angina requiring hospitalization) and severe angina (angina requiring revascularization).

Statistical analysis.

All subjects were included in the analysis using the intent-to-treat principle. Comparisons of baseline characteristics between treatment groups were made with the use of Student's t test for continuous variables and the chi-square test for categorical variables. We calculated the average annual event rates by dividing the observed number of events by the observed event-specific number of person-years of follow-up. We compared the event rates between treatment groups by determining the risk ratio (RR) in which the rate in the tamoxifen group was divided by the rate in the placebo group. The 95% confidence intervals (CIs) for the RR were determined assuming that the events followed a Poisson distribution, conditioning on the total number of events and person-years of follow-up. The cumulative incidence rates by time since randomization were also determined (10). Two-tailed P values <.05 or 95% CIs that did not include 1.0 were considered to be statistically significant.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Subjects

From June 1, 1992, through September 30, 1997, 13 388 women were randomly assigned to receive either tamoxifen or placebo as part of the NSABP BCPT (8). Of the 13 194 women for whom long-term follow-up is available, 1048 (7.9%) reported a history of myocardial infarction or angina prior to randomization and were classified as having a history of clinical CHD, while 12 146 women (92.1%) reported no such history. The clinical characteristics of the women with and without pre-existing clinical CHD are presented in Table 1Go. The subject demographics were not statistically significantly different between the tamoxifen and placebo cohorts in either of the subgroups (P values for data analysis not shown).


View this table:
[in this window]
[in a new window]
 
Table 1. Baseline characteristics of women with and without a baseline clinical history of coronary heart disease*
 
Cardiovascular Events

Cardiovascular event rates for the total population are shown in Table 2Go. Overall, the rates of cardiovascular events for the placebo and tamoxifen groups were similar. There were 72 events among the 6590 tamoxifen users and 68 among the 6604 women assigned to placebo. This represents an RR of 1.06 (95% CI = 0.75 to 1.49) for tamoxifen users. The rates and numbers of subjects for each of the specific types of cardiovascular events were also similar when compared by treatment group. No differences were noted for fatal myocardial infarction, nonfatal myocardial infarction, unstable angina, or severe angina. None of the RRs for these events were statistically significant, and all were close to unity.


View this table:
[in this window]
[in a new window]
 
Table 2. Cardiovascular event rates for women in the Breast Cancer Prevention Trial
 
Cardiovascular event rates for women with and without a history of clinical CHD are presented in Table 3Go. Among the 12 146 women without a history of clinical CHD, there were a total of 96 cardiovascular events (47 in the tamoxifen group and 49 in the placebo group). The RR comparing the total cardiovascular event rate in the tamoxifen group with that in the placebo group was 0.96 (95% CI = 0.63 to 1.46). There were also no statistically significant differences evident for any of the specific types of cardiovascular events. The RR among tamoxifen users for fatal or nonfatal myocardial infarction was 1.23 (95% CI = 0.67 to 2.31); for fatal myocardial infarction, it was 1.75 (95% CI = 0.44 to 8.13); for unstable angina, it was 0.69 (95% CI = 0.29 to 1.57); and for severe angina, it was 0.83 (95% CI = 0.32 to 2.10).


View this table:
[in this window]
[in a new window]
 
Table 3. Cardiovascular event rates among women in the Breast Cancer Prevention Trial stratified by those with and without a baseline history of coronary heart disease (CHD)
 
Cardiovascular event rates for the 1048 women with a history of clinical CHD also failed to show any statistically significant differences between the treatment groups (Table 3Go). Although the event rates in this cohort were, in general, greater than those observed in the group of women without a history of heart disease, these data demonstrate that assignment to tamoxifen did not affect cardiovascular events in this high-risk population. In this cohort of women, there were a total of 25 cardiovascular events in the tamoxifen group and 19 in the placebo group (RR = 1.39; 95% CI = 0.73 to 2.67). Similar findings were observed for individual cardiovascular events. The RR among tamoxifen users for fatal or nonfatal myocardial infarction was 0.69 (95% CI = 0.20 to 2.18); for fatal myocardial infarction, it was 0.00 (95% CI = 0 to 1.58); for unstable angina, it was 2.26 (95% CI = 0.87 to 6.55); and for severe angina, it was 1.39 (95% CI = 0.23 to 9.47).

To evaluate whether the lack of association between tamoxifen and cardiovascular risk was related to an early increase in risk that may have been offset by a late decrease in risk, as was seen in the Heart and Estrogen/progestin Replacement Study (HERS) of combined conjugated estrogens and medroxyprogesterone acetate in women with pre-existing CHD (6), we determined the cumulative incidence curves for combined cardiovascular events. Fig. 1Go demonstrates that there was no time trend in total cardiovascular events that could explain the observed lack of benefit of tamoxifen for cardiovascular disease prevention in our population of women without pre-existing clinical CHD. The cumulative incidence curves for the individual cardiovascular endpoints (total, fatal, and nonfatal myocardial infarction and unstable and severe angina) also failed to show a time trend of early increased and late decreased risks for these events (data not shown). The cumulative incidence curves for combined cardiovascular events in women with a history of clinical CHD also demonstrated that, in contrast to HERS, there was no temporal offsetting of an early adverse effect of tamoxifen by a late beneficial effect (Fig. 2Go). Similar findings were observed for individual cardiovascular endpoints in these women with pre-existing CHD (data not shown).



View larger version (22K):
[in this window]
[in a new window]
 
Fig. 1. Cumulative incidence curves for combined cardiovascular events in 12 146 women without a history of clinical coronary heart disease by assignment to tamoxifen versus placebo group.

 


View larger version (23K):
[in this window]
[in a new window]
 
Fig. 2. Cumulative incidence curves for combined cardiovascular events in 1048 women with a history of clinical coronary heart disease by assignment to tamoxifen versus placebo group.

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The overall benefit of prophylactic tamoxifen treatment in women is dependent on both its proven efficacy for breast cancer prevention (1) and its clinical cardiovascular effects. The importance of this consideration is suggested by HERS (6), which reported that a cohort of women with pre-existing CHD was at increased short-term risk for adverse cardiovascular events when treated with other types of hormones. Therefore, it is conceivable that there may be a high-risk cohort of women for whom a potentially adverse cardiovascular effect of tamoxifen outweighs its preventive effect on breast cancer.

It has been postulated that the effects of estrogen on CHD may serve as a paradigm for the cardiovascular effects of tamoxifen. Epidemiologic studies (1113), including the Nurses' Health Study (12), suggest that estrogen use is associated with a statistically significant decrease in CHD risk in healthy, relatively young postmenopausal women. This observation is biologically plausible because estrogen use is associated with a decrease in low-density lipoprotein (LDL) and an increase in high-density lipoprotein (HDL) cholesterol levels, both of which are associated with decreased cardiovascular risk (11,14). Estrogen also has lipid-independent anti-atherosclerotic properties that are associated with inhibition of diet-induced coronary artery intimal hyperplasia (15), acceleration of functional endothelial recovery in de-endothelialized arteries (16), and prevention of abnormal coronary vasoconstriction in women (17). However, despite these favorable pathophysiologic and epidemiologic effects of estrogen, the only reported large-scale, prospective placebo-controlled trial of postmenopausal hormones, HERS (6), demonstrated that conjugated estrogens plus medroxyprogesterone acetate use in women with established CHD was associated with a statistically significant increased risk of early (i.e., 1 year) cardiac death or myocardial infarction, although CHD risk tended to decrease in hormone users after the 4th year of follow-up. Therefore, a discrepancy exists between the pathophysiologic and clinical effects of traditional postmenopausal hormones in women with CHD.

Like estrogen, tamoxifen is expected to decrease cardiovascular risk because of its indirect and direct anti-atherosclerotic effects. Clinical trials have demonstrated that tamoxifen treatment decreases levels of total and LDL cholesterol and lipoprotein (a) and increases HDL subclass 2 levels (2,3). Indeed, although serial blood draws and analyses of lipid levels were not uniformly included as part of our BCPT, a substudy of 56 study participants (28 tamoxifen users and 28 placebo users) at the University of Vermont, Burlington, demonstrated that tamoxifen was associated with an approximately 10% reduction in total cholesterol levels (average change = 18 mg/dL after accounting for the change seen in the placebo group) after 6 months. In addition, animal studies (4,5) have shown that tamoxifen is associated with a reduction of arterial accumulation of LDL degradation products and inhibition of arterial intimal hyperplasia.

Tamoxifen also has estrogen antagonistic effects on the coronary vasculature that may contribute to the development of myocardial ischemia and offset its cardioprotective effects. Williams et al. (4) have shown that, when chronically administered to ovariectomized cynomolgus monkeys, tamoxifen failed to prevent inappropriate coronary vasoconstriction in response to acetylcholine, an endothelium-dependent vasodilator, and inhibited appropriate coronary dilatation in response to nitroglycerin. In addition, tamoxifen has prothrombotic properties that are clinically manifested by an increased risk for venous thromboembolic events (1). Because women with pre-existing heart disease likely have coronary atherosclerotic plaques that are predisposed to fissuring, instability, rupture, and thrombus formation, they may be expected to have an increased cardiovascular event rate when they are treated with tamoxifen due to thrombosis at sites of coronary atherosclerosis. Indeed, similar prothrombotic tendencies of steroid hormones have been offered as a potential explanation for the increased short-term cardiovascular event rate associated with combination conjugated estrogens and medroxyprogesterone acetate in women with pre-existing CHD who were enrolled in HERS (6,18).

Early breast cancer trials (1921) reported that tamoxifen was associated with decreased risks for fatal myocardial infarction, any myocardial infarction, and cardiac hospitalizations (1921). Such favorable cardiovascular effects of tamoxifen would support a widespread recommendation for tamoxifen use to prevent breast cancer in women. However, we reported previously that, among the 13 388 women studied in the NSABP BCPT, tamoxifen did not influence cardiovascular risk (1). The discrepancy between the results of the BCPT and those of previous trials may be related to differences in study design. For instance, subgroup analysis of cardiovascular mortality in the Scottish adjuvant tamoxifen trial (20) studied 1070 women who were older (mean age, 71 years) than the 13 388 women in our study. In addition, the Scottish study did not compare the distributions of cardiac risk factors between groups. The cardiovascular morbidity report of the Scottish tamoxifen trials (19) studied 1312 women who were of an age comparable to that of women in the NSABP BCPT (approximately 59 years) and demonstrated a lower incidence of hospital admission for acute myocardial infarction that was nearly statistically significant. However, the Scottish study relied on computerized information for coded diagnoses of hospital admissions for cardiovascular disease, in contrast to the NSABP BCPT, which tabulated cardiac events after blinded review of hospital records. The Stockholm Breast Cancer Study Group (21) reported the cardiovascular effects of tamoxifen in 2365 women with breast cancer, many of whom received adjuvant chemotherapy or radiation therapy that may have had independent adverse cardiovascular effects. The Stockholm study, which relied on a computerized register of hospital admissions, demonstrated that first hospitalization for "any cardiac disease" over a median of 6 years of follow-up was statistically significantly lower in women given only 2 years of adjuvant high-dose tamoxifen (40 mg daily). It is interesting that this observation was related to trends for lower event rates for hospitalization for angina, which was not confirmed by objective review of hospital records, and atrial fibrillation, which is frequently unrelated to CHD.

A potential explanation for the lack of cardiovascular effects of tamoxifen seen in our NSABP BCPT is that the beneficial cardiovascular effects of tamoxifen among women without prior heart disease may have been offset by a tamoxifen-associated increased cardiovascular risk among women with pre-existing CHD. This latter group of women is at high risk for cardiovascular events that is further increased by treatment with a traditional postmenopausal hormone combination of conjugated estrogens and medroxyprogesterone acetate (6). However, the results of the present study demonstrate that, during a mean follow-up of more than 4 years, tamoxifen does not statistically significantly alter risks for total cardiovascular events, fatal or nonfatal myocardial infarction, unstable angina, or severe angina in subgroups of women at risk for breast cancer that are categorized by history of clinical CHD. This observation may be explained by the complex interaction between tamoxifen's estrogenic and antiestrogenic properties that influence atherogenesis.

Our study has several potential limitations. First, the primary goal of our study was to determine the effectiveness of tamoxifen in preventing breast cancer. Evaluation of the cardiovascular effects of tamoxifen was a secondary goal of the study, which was designed a priori to collect information on baseline cardiac status and cardiovascular events during follow-up that were adjudicated by an endpoint committee blinded to treatment assignment. This assessment of cardiovascular risk was designed to determine the overall risk/benefit ratio of tamoxifen use in women who are at an increased risk for breast cancer. Because the primary study endpoint was the incidence of invasive breast cancer, the study was not primarily designed to optimize statistical power for detecting treatment differences in terms of CHD incidence. Although this may potentially limit the applicability of our findings and we cannot conclude with statistical certainty that there is no cardiac-related treatment effect, the issue of statistical power may be less relevant in this case because of the nature of the actual observed heart disease data. For instance, statistical power would be a particular concern if a heart disease effect of reasonable magnitude were present, but not statistically significant, in this study. However, the data presented in this study demonstrate that the numbers of total and disease-specific CHD events were essentially the same in both the tamoxifen and placebo groups. Furthermore, while the statistical power for detecting differences in the subset analysis of women with CHD is reduced, this analysis addresses the possibility that tamoxifen may exhibit an early detrimental effect similar to that seen for traditional hormones in HERS. However, the data for both subsets are consistent with a null hypothesis of no overall treatment effect for heart disease and do not provide support for a temporally related detrimental effect. Nevertheless, all post-hoc subset analyses should be viewed with caution.

An additional limitation in our study is that the subgroup of women with prior heart disease was defined by self-report of angina or prior myocardial infarction and not by diagnostic coronary angiography. Although this might be perceived as a limitation, our classification is similar to classifications used by other large-scale epidemiologic studies; our results are generalizable to clinical practice that does not subject women to coronary angiography prior to initiation of tamoxifen for breast cancer prevention. Our exploratory study represents, to our knowledge, the largest reported cardiovascular study of a nonsteroid hormone-related compound in women.

Finally, the duration of follow-up in our study may have been inadequate to detect longer term cardiovascular events in a relatively young cohort. However, the duration of follow-up was similar to that of both the early Nurses' Health Study follow-up, which demonstrated a beneficial effect of estrogen in a group of similarly aged women, and the HERS trial (6,22). In addition, our large sample size of women without a history of heart disease optimized the likelihood of detecting early events. Nevertheless, additional follow-up of our cohort of women is ongoing to determine whether tamoxifen has a longer term cardiovascular effect. Because unblinding of our study may have potentially resulted in a crossover of placebo patients to clinically indicated tamoxifen treatment, which would influence the assessment of initial treatment assignment on cardiovascular events, it is important to evaluate cardiovascular event rates in other long-term, large-scale, prospective clinical trials of tamoxifen, such as the International Breast Cancer Intervention Study.

In conclusion, this randomized, placebo-controlled, double-blinded study found that tamoxifen does not statistically significantly alter cardiovascular risk during 4 years of follow-up in women at risk for breast cancer. The lack of a clinical cardiovascular effect of tamoxifen in women is independent of the presence or absence of pre-existing clinical CHD. Therefore, the overall clinical effect of tamoxifen in women with and without heart disease is related to breast cancer prevention and is independent of tamoxifen's cardiovascular effects. The lack of a clinical cardioprotective effect of tamoxifen also suggests that tamoxifen-associated lipid lowering is not an accurate surrogate marker for the reduction of clinical heart disease. Because tamoxifen is being prescribed increasingly for the prevention and treatment of breast cancer, longer term clinical trials of tamoxifen in women are needed to further elucidate its long-term cardiovascular effects.


    NOTES
 
Editor's note: M. Kavanah and D. L. Wickerham are members of the speaker's bureau of Astra Zeneca, the manufacturer of tamoxifen.

Supported by Public Health Service grants U10CA37377 and U10CA69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

1 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.[Abstract/Free Full Text]

2 Morales M, Santana N, Soria A, Mosquera A, Ordovas J, Novoa J, et al. Effects of tamoxifen on serum lipid and apolipoprotein levels in postmenopausal patients with breast cancer. Breast Cancer Res Treat 1996;40:265–70.[Medline]

3 Vrbanec D, Reiner Z, Belev B, Plestina S. Changes in serum lipid and lipoprotein levels in postmenopausal patients with node-positive breast cancer treated with tamoxifen. Tumori 1998;84:687–90.[Medline]

4 Williams JK, Honore EK, Adams MR. Contrasting effects of conjugated estrogens and tamoxifen on dilator responses of atherosclerotic epicardial coronary arteries in nonhuman primates. Circulation 1997;96:1970–5.[Abstract/Free Full Text]

5 Williams JK, Wagner JD, Li Z, Golden DL, Adams MR. Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys. Arterioscler Thromb Vasc Biol 1997;17:403–8.[Abstract/Free Full Text]

6 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.[Abstract/Free Full Text]

7 American Heart Association. Heart and stroke facts: 1999 statistical supplement. Dallas (TX): American Heart Association; 1999.

8 Fisher B, Costantino J. Highlights of the NSABP Breast Cancer Prevention Trial. Cancer Control 1997;4:78–86.[Medline]

9 Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879–86.[Abstract]

10 Korn EL, Dorey FJ. Applications of crude incidence curves. Stat Med 1992;11:813–29.[Medline]

11 Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987;75:1102–9.[Abstract]

12 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study. N Engl J Med 1991;325:756–62.[Abstract]

13 Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47–63.[Medline]

14 The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199–208.[Abstract]

15 Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS, Wolfe MS, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051–7.[Abstract]

16 Krasinski K, Spyridopoulos I, Asahara T, van der Zee R, Isner JM, Losordo DW. Estradiol accelerates functional endothelial recovery after arterial injury. Circulation 1997;95:1768–72.[Abstract/Free Full Text]

17 Reis SE, Gloth ST, Blumenthal RS, Resar JR, Zacur HA, Gerstenblith G, et al. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation 1994;89:52–60.[Abstract]

18 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801–11.[Free Full Text]

19 McDonald CC, Alexander FE, Whyte BW, Forrest AP, Stewart HJ. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. BMJ 1995;311:977–80.[Abstract/Free Full Text]

20 McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee. BMJ 1991;303:435–7.[Medline]

21 Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993;85:1398–406.[Abstract]

22 Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985;313:1044–9.[Abstract]

Manuscript received June 5, 2000; revised October 17, 2000; accepted October 26, 2000.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement