Hormone Replacement Therapy and the Risk of Myocardial Infarction in Women with Coronary Risk Factors
Petitti, Diana B.1; Sidney, Stephen2; Quesenberry, Charles P. Jr.2
From the 1Kaiser Permanente Medical Care Program, Southern California, Pasadena, CA, and 2Northern California, Oakland, CA.
This research was supported by grant number R01-HL-47043 from the National Heart Lung and Blood Institute.
Submitted November 4, 1999; final version accepted February 29, 2000.
Address reprint requests to: Diana Petitti, 393 E. Walnut Street, Pasadena, CA 91188.
To assess the risk of myocardial infarction in users of post-menopausal hormone replacement therapy who are at high risk of coronary disease because of hypertension, diabetes mellitus, or smoking, we used data from a previously published case-control study of women 45–74 years. After adjustment for age, ethnicity, and education, the odds ratio for myocardial infarction in current users of hormone replacement therapy was 0.9 (95% confidence interval (CI) = 0.5–1.6) in women with no major coronary risk factors, 0.8 (95% CI = 0.5–1.8) in women with one risk factor, and 1.1 (95% CI = 0.5–2.2) in women with two risk factors.
Only one large randomized trial, the Heart and Estrogen/Progestin Replacement Study (HERS), has examined the effect of post-menopausal hormone use on coronary heart disease (CHD) endpoints. 1 It found no overall benefit of combined estrogen/progestin hormone replacement therapy for secondary prevention of CHD in women with coronary disease. HERS results were surprising because a large body of observational data suggests that estrogen replacement therapy and estrogen plus progestin replacement therapy prevent CHD. 2–26
HERS authors hypothesized that an early adverse prothrombic effect of estrogen-progestin that is counterbalanced by a later, beneficial anti-atherogenic effect of estrogen-progestin might explain their results. 1 The HERS results cannot be extrapolated to hormones for primary prevention of CHD because women without coronary disease may not be susceptible to the putative prothrombic effect of female hormones. 1,27
In HERS, the risk of CHD events was increased in the 1st year after initiation of estrogen-progestin use. 1 This finding has raised questions about initiation of estrogen-progestin use in women at high risk of CHD because of coronary risk factors. Models show that the increase in life expectancy in estrogen and estrogen-progestin users at high risk of CHD would be large if the effect of estrogen and estrogen-progestin is as large as reported in observational studies. 28,29
In this analysis of data from a previously published case-control study that examined the relative risk of incident myocardial infarction (MI) in current and past users of estrogen and estrogen-progestin, 23 we examined the relative risk of incident acute MI in current users of estrogen and estrogen-progestin according to major risk factors for CHD.
The study methods were described elsewhere. 23 Cases were women, 45–74 years of age, hospitalized for MI in one of 10 Kaiser Permanente Northern California hospitals between November 1991 and November 1994. Included are definite or probable cases based on American Heart Association Council on Epidemiology diagnostic criteria. 30
One age-matched and facility-matched control was identified for each case. All subjects were interviewed in person. For cases that had died or could not communicate, we interviewed a proxy. Proxy information was excluded, however, because proxies underreported hormone use that was documented in medical records. 23
We considered hypertension, diabetes mellitus, high cholesterol (self-reported as such) and current regular cigarette smoking to be major CHD risk factors. Subjects were classified as having hypertension and diabetes if they answered “yes” to questions about medication use for these conditions and high cholesterol if a doctor had told them they had high cholesterol. We excluded women who reported a previous heart attack or angina from this analysis. We also restricted the analysis to post-menopausal women, as defined in our earlier publication. 23
Among hormone users, the vast majority of hysterectomized women used estrogen only (50.6% vs. 1.2% who used estrogen-progestin) and most non-hysterectomized women used estrogen-progestin (18.4%vs 3.0% who used estrogen). Because odds ratio (OR) estimates for MI in hysterectomized estrogen-progestin users and non-hysterectomized estrogen users were unstable statistically, we excluded these categories of users, as well as women of unknown hysterectomy status and the small number of users of progestin only. We defined current hormone use as positive for hysterectomized current estrogen users or non-hysterectomized current estrogen-progestin users and “no” otherwise. Users of only hormone creams were classified as “no.”
We estimated the odds ratio (OR) of MI in current users compared with non-current estrogen and estrogen-progestin users according to the number of major CHD risk factors. We used non-current users of estrogen and estrogen-progestin as the referent because three of the four published studies that have assessed this association, 10,21,23 including the Nurses’ Health Study, 10 have shown no effect of estrogen and estrogen-progestin on the risk of MI after use ceases.
Because matched analysis causes substantial loss of case-control pairs, we used unconditional logistic regression. We adjusted for age and education, as measures of socioeconomic status, and race/ethnicity because the risk of coronary heart disease varies by race/ethnicity. 31
We identified 735 possible MI cases; 685 cases were considered definite or probable MI. Exclusions left 410 cases and 411 controls for the analysis (Table 1). Of hormone users, 97% used conjugated equine estrogen, esterified estrogen, or ethinyl estradiol. Table 2 shows the characteristics of cases and controls and the ORs for MI for each characteristic of the estrogen-progestin users. The overwhelming majority of users of estrogen-progestin (95%) took medroxyprogesterone acetate. The estrogen-progestin regimens were diverse and included continuous use in several doses and intermittent use for 7, 10, and 14 days.
Table 3 shows the adjusted OR for MI according to the number of major cardiovascular risk factors. The referent in this analysis is women with no major CHD risk factors. The OR for MI increased with increasing number of risk factors, although the 95% confidence intervals (CI) for two risk factors overlapped that for one risk factor and the CI for three risk factors overlapped that for two. Among women with only one CHD risk factor, the highest OR for MI was for diabetes mellitus, but the CI for MI in women with diabetes overlapped that for smoking and hypercholesteremia.
Table 4 shows the adjusted OR in current estrogen and estrogen-progestin users compared with non-current users of estrogen or estrogen-progestin by number of major CHD risk factors and, for women with only one major CHD risk factor, the ORs for MI by risk factor. The referent is women with the same number of risk factors who were non-current users of estrogen and estrogen-progestin. The adjusted OR for MI in current estrogen and estrogen-progestin users was 0.9 (95% CI = 0.5–1.6) in women with no major CHD risk factors, 0.8 (95% CI = 0.5–1.4) in women with one major CHD risk factor, and 1.1 (95% CI = 0.5–2.2) in women with two major CHD risk factors. Among women with only one major CHD risk factor, the largest decrease in the OR in current estrogen and estrogen-progestin users was in women with hypertension only (OR 0.6; 95% CI = 0.3–1.5). The OR for MI in current users of estrogen and estrogen-progestin with diabetes mellitus only was 2.0 (95% CI = 0.2–27.6). Confidence intervals for all OR estimates in current users of estrogen and estrogen-progestin were wide.
We found that the risk of MI in current users of estrogen and estrogen-progestin was nearly the same in women with no, one, two, and three major CHD risk factors. Confidence intervals remain wide even when risk factors were grouped according to their number.
Hulley et al1 mentioned that, in HERS, there was “no clear evidence of differential effects of estrogen-progestin for a large number of variables.” Relative risk estimates were not presented in subgroups. Rosenberg et al21 reported relative risk estimates for MI in current, long-term (≥5 years) estrogen users of 0.5 for never-smokers, 1.0 for light (<25 cigarettes/day) smokers, and 0.5 for heavy smokers (≥25 cigarettes/day). Relative risk estimates in women with diabetes and hypertension were not presented. Grodstein et al10 estimated the relative risk of CHD (fatal CHD and MI) in current hormone users according to smoking status (current/not current), blood pressure (high/normal), and cholesterol level (high/normal). In their analysis, after adjustment for age, time since menopause, body mass index, diabetes, past oral contraceptive use, parental history of MI, type of menopause and the major CHD risk factors not being examined (eg, blood pressure and cholesterol were adjusted when examining smoking), the effect of current hormone use was about the same amount (RR 0.43 to 0.68) in all subgroups. The relative risk of MI in current estrogen users with diabetes mellitus only was not presented.
Eventually the Women’s Health Initiative, 32 a large randomized trial examining whether conjugated estrogen and continuous conjugated estrogen combined with medroxyprogesterone acetate are effective in the primary prevention of CHD, may illuminate whether women at high risk of CHD because of hypertension, diabetes mellitus, smoking, or hypercholesterolemia should be managed like women with established coronary disease or like women free of CHD. Still, this question will be difficult to answer definitively. Although our study had a fairly large number of cases and a high prevalence of estrogen and estrogen-progestin use, the number of women in subgroups defined by number of CHD risk factors or by specific risk factor among those with only one risk factor was small, and estimates of the effect of MI current user of estrogen and estrogen-progestin for MI had a high degree of uncertainty.
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© 2000 Lippincott Williams & Wilkins, Inc.
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