Petitti, Diana B.1; Sidney, Stephen2; Quesenberry, Charles P. Jr.2
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.
1. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605–613.
2. Adam S, Williams V, Vessey M. Cardiovascular disease and hormone replacement treatment: a pilot case-control study. BMJ 1981; 282: 1277–1278.
3. Avila MH, Walker AM, Jick H. Use of replacement estrogens and the risk of myocardial infarction. Epidemiology 1990; 1: 128–133.
4. Bain C, Willett WC, Hennekens CH, Rosner B, Belanger C, Speizer FE. Use of postmenopausal hormones and risk of myocardial infarction. Circulation 1981; 64: 42–46.
5. Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75: 1102–1109.
6. Byrd BF, Burch JC, Vaughn WK. The impact of long term estrogen support after hysterectomy. A report of 1016 cases. Ann Surg 1977; 185: 574–580.
7. Criqui MH, Suarez L, Barrett-Connor E, McPhillips J, Wingard DL, Garland C. Postmenopausal estrogen use and mortality: results from a prospective study in a defined, homogenous community. Am J Epidemiol 1988; 128: 606–614.
8. Ettinger B, Friedman GD, Bush T, Quesenberry CP Jr. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol 1996; 87: 6–12.
9. Falkeborn M, Persson I, Adami H-O, Bergstrom R, Eaker E, Lithell H, Mohsen R, Naessen T. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 1992; 99: 821–828.
10. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335:453–461. [Published erratum appears in N Engl J Med 1996;335:1406].
11. Hammond CB, Jelovesk FR, Lee KL, Creasman WT, Parker RT. Effects of long-term estrogen replacement therapy. I. Metabolic effects. Am J Obstet Gynecol 1979; 133: 525–536.
12. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991; 151: 75–78.
13. MacMahon B. Cardiovascular disease and noncontraceptive oestrogen therapy. In: Oliver MF, ed. Coronary Heart Disease in Young Women. New York: Churchill Livingston, 1978; 197–207.
14. Mann RD, Lis Y, Chukwujindy J, Chanter DO. A study of the association between hormone replacement therapy, smoking and occurrence of myocardial infarction in women. J Clin Epidemiol 1994; 47: 307–312.
15. O’Brien JE, Peterson ED, Keeler GP, Berdan LG, Ohman EM, Faxon DP, Jacobs AK, Topol EJ, Califf RM. Relation between estrogen replacement therapy and restenosis after percutaneous coronary interventions. J Am Coll Cardiol 1996; 28: 1111–1118.
16. O’Keefe JH, Kim SC, Hall RR, Cochran VC, Lawhorn SL, McCallister BD. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol 1997; 29: 1–5.
17. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol 1987; 70: 289–293.
18. Pfeffer RI, Whipple GH, Kurosaki TT, Chapman JM. Coronary risk and estrogen use in postmenopausal women. Am J Epidemiol 1978; 107: 479–487.
19. Psaty BM, Heckbert SR, Atkins D, Lemaitre R, Koepsell TD, Wahl PW, Siscovick DS, Wagner EH. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med 1994; 154: 1333–1339.
20. Rosenberg L, Armstrong B, Jick H. Myocardial infarction and estrogen therapy in post-menopausal women. N Engl J Med 1976; 294: 1256–1259.
21. Rosenberg L, Palmer JR, Shapiro S. A case-control study of myocardial infarction in relation to use of estrogen supplements. Am J Epidemiol 1993; 137: 54–63.
22. Ross RK, Paganini-Hill A, Mack TM, Arthur M, Henderson BE. Menopausal oestrogen therapy and protection from death from ischemic heart disease. Lancet 1981; 1: 858–860.
23. Sidney S, Petitti DB, Quesenberry CP. Myocardial infarction and the use of estrogen and estrogen-progestogen in postmenopausal women. Ann Intern Med 1997; 127: 501–508.
24. Sullivan JM, El-Zeky F, Vander Zwaag R, Ramanathan KB. Effect on survival of estrogen replacement therapy after coronary artery bypass grafting. Am J Cardiol 1997; 79: 847–850.
25. Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, Mirvis DM. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med 1990; 150: 2257–2562.
26. Talbott E, Kuller LH, Detre K, Perper J. Biologic and psychosocial risk factors of sudden death from coronary disease in white women. Am J Cardiol 1977; 39: 858–864.
27. Petitti DB. Hormone replacement therapy and heart disease prevention: experimentation trumps observation. JAMA 1998; 280: 651–653.
28. Col NF, Eckman MH, Karas RH, Pauker SG, Goldberg RJ, Ross EM, Orr RK, Wong JG. Patient-specific decisions about hormone replacement therapy in postmenopausal women. JAMA 1997; 277: 1140–1147.
29. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016–1037.
30. Gillum RF, Fortmann S, Prineas RJ, Kottke TE. International diagnostic criteria for myocardial infarction and acute stroke. (Prepared for the Committee on Criteria and Methods, Council on Epidemiology, American Heart Association). Am Heart J 1984; 108: 150–158.
31. Gillum RF. Cardiovascular disease in the United States: an epidemiologic overview. In: Saunders E, Brest AN, eds. Cardiovascular Diseases in Blacks. Philadelphia: FA Davis, 1991; 3–16.
32. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998; 19: 61–109.
© 2000 Lippincott Williams & Wilkins, Inc.